Crystalline forms of isoxazoline compounds

Abstract

The present disclosure provides crystalline forms of 2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide, methods for preparing same, and pharmaceutical compositions containing same.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED PATENT APPLICATIONS This patent application is an international patent application that claims priority to PCT Application No. PCT / CN2021 / 100305, filed on June 16, 2021, the disclosure of each of which is incorporated herein by reference in its entirety.

[0002] The present invention relates to crystalline forms of isoxazoline compounds of formula 1, methods for preparing same, and pharmaceutical compositions comprising same. More particularly, the present invention relates to crystalline forms of 2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide, methods for preparing same, and pharmaceutical compositions comprising same. [ka] [Background technology]

[0003] U.S. Patent Application No. 17 / 125,365 ("US'365") and International Patent Application No. PCT / US20 / 65624 (published as WO 2021 / 127188; "WO'188") disclose 2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide of formula 1 ("Compound of Formula 1"), and pharma- ceutical acceptable salts thereof, having sustained half-life in the treatment and control of pests (particularly fleas, ticks, mites, flies, worms, and lice) of animals (particularly warm-blooded animals and fish).

[0004] US'365 and WO'188 also disclose methods for preparing the compound of formula 1 as well as its R-enantiomer. The compound of formula 1 produced by the methods described in US'365 and WO'188 is amorphous. However, when attempts were made to implement a scaled-up process based on the methods disclosed in US'365 and WO'188, the compound of formula 1 was obtained in an amorphous form rather than a crystalline solid. Such amorphous forms are less desirable for commercial production because they are less pure and more hygroscopic compared to the crystalline solid. Summary of the Invention

[0005] One aspect of the present invention is to provide one or more crystalline forms of the compound of formula 1 that have improved (i.e., reduced) hygroscopicity and improved purity, and are more suitable for large-scale (i.e., industrial-scale or large-scale) production.

[0006] Another aspect is to provide pharmaceutical compositions containing one or more crystalline forms of the compound of formula 1.

[0007] Another aspect is to provide a method for preparing one or more crystalline forms of the compound of formula 1.

[0008] Other objects and advantages of the present invention will become apparent from the following detailed description of the invention, taken together with the appended claims. Since specific contents not described in this specification can be fully recognized and inferred by those skilled in the art of the present invention or similar fields, the description thereof will be omitted.

[0009] In one aspect of the invention, there is provided crystalline form A (also referred to as "crystalline form I") of the compound of formula 1, characterized in that form A exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 18.1°, 19.5°, and 22.3° ±0.2°.

[0010] In one aspect of the invention, there is provided crystalline form B (also referred to as "crystalline form II") of the compound of formula 1, characterized in that the crystalline form B exhibits an X-ray powder diffraction (XRPD) pattern including peaks at 2θ values ​​of 3.5°, 19.2°, and 22.3° ±0.2°.

[0011] In one aspect of the present invention, there is provided crystalline form C (also referred to as "crystalline form III") of the compound of formula 1, characterized in that the crystalline form C exhibits an X-ray powder diffraction (XRPD) pattern including peaks at 2θ values ​​of 4.6°, 20.5°, and 21.7° ±0.2°.

[0012] In another embodiment, there is provided a pharmaceutical composition comprising one or more crystalline forms of the compound of Formula 1 as an active ingredient and at least one pharma- ceutically acceptable carrier or diluent.

[0013] In another embodiment, there is provided a method for preparing crystalline form A of the compound of formula 1, comprising the steps of:

[0014] Dissolving the compound of formula 1 in component A, optionally with stirring and / or heating, where component A is an organic solvent suitable for dissolving the compound of formula 1, non-limiting examples of which include C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, ethyl lactate, isopropyl acetate, heptane, n-heptane, isobutyl acetate, methyl ethyl ketone (MEK), methanol, medium chain triglycerides (e.g., MIGLYOL® 812), N-methyl-2-pyrrolidone (NMP), 1-octanol, 1-propanol, 2-propanol, methyl tert-butyl ether (TBME), tetrahydrofuran (THF ... and one or more of furan (THF), toluene, and triethylamine. Preferred non-limiting examples of component A include one or more of C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, ethyl lactate, isopropyl acetate, isobutyl acetate, methyl ethyl ketone (MEK), methanol, medium chain triglycerides (e.g., MIGLYOL® 812), N-methyl-2-pyrrolidone (NMP), 1-octanol, 1-propanol, 2-propanol, methyl tert-butyl ether (TBME), tetrahydrofuran (THF), toluene, and triethylamine.

[0015] Optionally, component B is added, which is a poor solvent that reduces the solubility of the mixture. Non-limiting examples of component B include water and C5-C 12 adding one or more of cyclic or acyclic hydrocarbon alkanes (e.g., cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably one or more of water and heptane;

[0016] Optionally, distilling off one or more components A and, if present, one or more components B;

[0017] and filtering the resulting solid.

[0018] In one embodiment, the compound of formula 1 dissolved in the dissolving step can be in amorphous form, crystalline form, or a combination thereof. In another embodiment, the compound of formula 1 dissolved in the dissolving step is in amorphous form. In another embodiment, component B (i.e., anti-solvent) is present.

[0019] In another embodiment, there is provided a method for preparing crystalline form B of the compound of formula 1, comprising the steps of:

[0020] Dissolving the compound of formula 1 in component A, optionally with stirring and / or heating, where component A is an organic solvent suitable for dissolving the compound of formula 1, non-limiting examples of which include C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, n-heptane, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, and one or more of TBME, THF, toluene, and triethylamine. Preferred non-limiting examples of component A include one or more of C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine.

[0021] Optionally, component B is added, which is a poor solvent that reduces the solubility of the mixture. Non-limiting examples of component B include water and C5-C 12adding one or more of cyclic or acyclic hydrocarbon alkanes (e.g., cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably one or more of water and heptane;

[0022] distilling off one or more components A and, if present, one or more components B;

[0023] and filtering the resulting solid.

[0024] In one embodiment, the compound of formula 1 dissolved in the dissolving step can be in amorphous form, crystalline form, or a combination thereof. In another embodiment, the compound of formula 1 dissolved in the dissolving step is in amorphous form. In another embodiment, component B (i.e., anti-solvent) is present.

[0025] In another embodiment, there is provided a method for preparing crystalline form C of the compound of formula 1, comprising the steps of:

[0026] Dissolving the compound of formula 1 in one or more components A, optionally with stirring and / or heating, where component A is an organic solvent suitable for dissolving the compound of formula 1, non-limiting examples of which include C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, n-heptane, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, and the like. and one or more of C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine.

[0027] Adding one or more components B, which are poor solvents that reduce the solubility of the mixture. Non-limiting examples of component B include water and C5-C 12 adding a cyclic or acyclic hydrocarbon alkane (e.g., cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably one or more of water and heptane;

[0028] Optionally, distilling off one or more components A and one or more components B.

[0029] Optionally, adding and distilling off additional component B; and filtering the resulting solid.

[0030] In one embodiment, the compound of formula 1 dissolved in the dissolving step can be in amorphous form, crystalline form, or a combination thereof. In another embodiment, the compound of formula 1 dissolved in the dissolving step is in amorphous form.

[0031] In another embodiment, there is provided crystalline forms A, B, or C of the compound of formula 1 prepared by the methods described above.

[0032] In another embodiment of any of the above methods, component B (i.e., an anti-solvent) is present. [Brief description of the drawings]

[0033] [Figure 1] FIG. 1 shows the powder X-ray diffraction (XRPD) pattern of Sample 1 (amorphous 2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide.

[0034] [Diagram 2] FIG. 2 shows the thermograms generated by thermogravimetry coupled with Fourier transform infrared spectroscopy (TG-FTIR) performed on sample 1 up to 350° C. at a heating rate of 10° C. / min.

[0035] [Diagram 3] FIG. 3 shows the differential scanning calorimetry (DSC) curve of Sample 1 up to 250° C. at a heating rate of 10° C. / min.

[0036] [Figure 4] Figure 4 shows the dynamic moisture sorption / desorption (DVS) isotherms for Sample 1. The changes in moisture content (thin line) and relative humidity (thick line) are shown as a function of time. The moisture content is calculated from the mass change of the sample during the DVS measurement.

[0037] [Diagram 5] Figure 5 shows the DVS isotherm of sample 1. The change in moisture content is shown as a function of relative humidity. The moisture content is calculated from the mass change of the sample during the DVS measurement.

[0038] [Figure 6] Figure 6 shows an overlay of the XRPD patterns of Sample 1 before DVS (trace A, top) and after DVS measurement (trace B, bottom). The diffractograms are offset in the y-axis direction for comparison purposes.

[0039] [Figure 7] FIG. 7 shows an overlay of XRPD patterns of samples, from bottom to top: samples 2 (trace I), 3 (trace H), 4 (trace G), 5 (trace F), 6 (trace E), 7 (trace D), 11a-2 measured under Kapton film (trace C), 20 (trace B), and 12a measured under Kapton film (trace A), all samples in FIG. 7 being crystalline form A. The broad peak at 5.6° 2θ in some of the diffractograms is assigned to the Kapton film. The diffractograms are offset in the y-axis direction for comparison purposes.

[0040] [Figure 8] Figure 8 shows an overlay of XRPD patterns of samples, from bottom to top: samples 8 (trace C), 10 (trace B), and 26 (trace A), all samples in Figure 8 are crystalline form B. The diffractograms are offset in the y-axis direction for comparison purposes.

[0041] [Figure 9] Figure 9 shows an overlay of the XRPD patterns of samples, from bottom to top: Sample 2 (trace B), and 10 (trace A). Sample 2 is crystalline form A and sample 10 is crystalline form B. The arrows point out the differences between the two XRPD patterns. The diffractograms are offset in the y-axis direction for comparison purposes.

[0042] [Figure 10] FIG. 10 shows the TG-FTIR thermogram performed on sample 2a (crystalline form A after drying).

[0043] [Figure 11] FIG. 11 shows the TG-FTIR thermogram performed on sample 10a (crystalline form B after drying).

[0044] [Figure 12] FIG. 12 shows the TG-FTIR thermogram performed on sample 13a (a mixture of crystalline forms A and B).

[0045] [Figure 13] FIG. 13 shows the XRPD pattern of Sample 2 (crystalline form A).

[0046] [Figure 14] FIG. 14 shows an overlay of XRPD patterns acquired during the crystallization experiment. Samples are numbered from bottom to top as 2 (trace P), 2a (trace O), 3 (trace N), 4 (trace M), 5 (trace L), 6 (trace K), 7 (trace J), ​​14 (trace I), 15 (trace H), 17 (trace G), 18 (trace F), 19 (trace E), 20 (trace D), 21 (trace C), 23 (trace B), and 28 (trace A). The broad reflection at approximately 5.6° 2θ for sample 23 corresponds to the signal of the Kapton film used to measure wet sample 23. The diffractograms are offset in the y-axis direction for comparison purposes.

[0047] [Figure 15] FIG. 15 shows the DSC curve of sample 2a of crystalline form A after drying.

[0048] [Figure 16]Figure 16 shows the DVS isotherms for sample 2a. The change in moisture content (light line) and relative humidity (bold line) are shown as a function of time. The moisture content is calculated from the mass change of the sample during the DVS measurement.

[0049] [Figure 17] Figure 17 shows the DVS isotherm of sample 2a. The change in moisture content is shown as a function of relative humidity. The moisture content is calculated from the mass change of the sample during the DVS measurement.

[0050] [Figure 18] Figure 18 shows an overlay of the XRPD patterns of sample 2a (crystalline form A) before (trace B, bottom) and after (trace A, top) DVS measurements. The diffractograms are offset in the y-axis direction for comparison purposes.

[0051] [Figure 19] FIG. 19 shows the XRPD pattern of Sample 10 (crystalline form B).

[0052] [Figure 20] FIG. 20 shows the DSC curve of sample 10a of crystalline form B after drying.

[0053] [Figure 21] FIG. 21 shows the DSC curve of sample 30a of crystalline form B after drying.

[0054] [Figure 22] Figure 22 shows the DVS isotherm of sample 10 (crystalline form B). The change in water content (thin line) and relative humidity (thick line) are shown as a function of time. The water content is calculated from the mass change of the sample during the DVS measurement.

[0055] [Figure 23] Figure 23 shows the DVS isotherm of sample 10 (crystalline form B). The change in water content is shown as a function of relative humidity. The water content is calculated from the mass change of the sample during the DVS measurement.

[0056] [Figure 24] Figure 24 shows an overlay of the XRPD patterns of sample 10 (crystalline form A) before (trace B, bottom) and after (trace A, top) DVS measurements. The diffractograms are offset in the y-axis direction for comparison purposes.

[0057] [Diagram 25] Figure 25 shows an overlay of XRPD patterns obtained during mechanical loading experiments, measurements were performed using a D8 Advance (Bruker ASX, Germany) analyzer. Samples numbered from bottom to top are 37 (trace D, authentic form A), 38 (trace C, form A after grinding), 39 (trace B, form A after ball milling), and 40 (trace A, form A after pressing at 15 bar). The diffractograms are offset in the y-axis direction for comparison purposes.

[0058] [Figure 26] Figure 26 shows an overlay of XRPD patterns obtained during mechanical loading experiments, measured using a D8 Advance (Bruker ASX, Germany) analyzer, with sample numbers 37 (trace B, authentic form A) and 38 (trace A, form A after grinding).

[0059] [Figure 27] Figure 27 shows an overlay of XRPD patterns obtained during mechanical loading experiments, measured using a D8 Advance (Bruker ASX, Germany) analyzer, with sample numbers 37 (trace B, authentic form A) and 39 (trace A, ball-milled form A).

[0060] [Figure 28]Figure 28 shows an overlay of XRPD patterns obtained during mechanical loading experiments, measured using a D8 Advance (Bruker ASX, Germany) analyzer, with sample numbers 37 (trace B, authentic form A) and 40 (trace A, form A after pressing at 15 bar).

[0061] [Figure 29] FIG. 29 shows the XRPD pattern of sample 2a (crystalline form A) with peak picking.

[0062] [Diagram 30] FIG. 30 shows the XRPD pattern of sample 10a (crystalline form B) with peak picking.

[0063] [Diagram 31] FIG. 31 shows the solubility of crystalline form A in ethyl acetate / heptane 1:3 (curve A), 2-propanol / water 1:1 (curve B), and TBME / heptane 1:1 (curve C) as a function of temperature.

[0064] [Diagram 32] FIG. 32 shows a plot of the natural logarithm of the solubility of crystalline form A in ethyl acetate / heptane 1:3 versus the inverse temperature (in Kelvin).

[0065] [Diagram 33] FIG. 33 shows a plot of the natural logarithm of the solubility of crystalline form A in 2-propanol / water 1:1 versus the inverse of temperature (in Kelvin).

[0066] [Diagram 34] FIG. 34 shows a natural log plot of the solubility of crystalline form A in TBME / heptane 1:1 versus the inverse temperature (in Kelvin).

[0067] [Diagram 35]FIG. 35 shows optical microscope images from sample 43 (form A + small amount of form B) as neat powder (left) and suspended in paraffin oil (right).

[0068] [Diagram 36] FIG. 36 shows optical microscope images from Sample 44 (crystal form A) as neat powder (left) and suspended in paraffin oil (right).

[0069] [Figure 37] FIG. 37 shows optical microscope images from Sample 45 (crystal form A) as neat powder (left) and suspended in paraffin oil (right).

[0070] [Figure 38] FIG. 38 shows optical microscope images from Sample 46 (crystal form A) as neat powder (left) and suspended in paraffin oil (right).

[0071] [Figure 39] FIG. 39 shows optical microscope images from sample 47 (crystal form A) as neat powder (left) and suspended in paraffin oil (right).

[0072] [Diagram 40] FIG. 40 shows optical microscope images from sample 48 (crystal form A) as neat powder (left) and suspended in paraffin oil (right).

[0073] [Diagram 41] FIG. 41 shows optical microscope images from Sample 49 (crystal form A) as neat powder (left) and suspended in paraffin oil (right).

[0074] [Diagram 42] FIG. 42 shows optical microscope images from sample 50 (crystal form A) as neat powder (left) and suspended in paraffin oil (right).

[0075] [Diagram 43] FIG. 43 shows optical microscope images from sample 51 (crystal form A) as neat powder (left) and suspended in paraffin oil (right).

[0076] [Diagram 44] FIG. 44 shows optical microscope images from sample 52 (crystal form A) as neat powder (left) and suspended in paraffin oil (right).

[0077] [Diagram 45] FIG. 45 shows optical microscope images from sample 42 (crystal form A) used for seeding in small scale experiments, neat powder (left) and suspended in paraffin oil (right).

[0078] [Figure 46] Figure 46 shows an overlay of XRPD patterns of samples, from bottom to top: sample 43 (trace C, mixture of forms A and B), 42 (trace B, form A), and 10 (trace A, form B). The arrow indicates the peak of form B observed in the diffractogram of sample 43. The diffractograms are offset in the y-axis direction for comparison purposes.

[0079] [Figure 47] Figure 47 shows an overlay of XRPD patterns of the samples, which are, from bottom to top, samples 42 (trace K), 43 (trace J), ​​44 (trace I), 45 (trace H), 46 (trace G), 47 (trace F), 48 (trace E), 49 (trace D), 50 (trace C), 51 (trace B), and 52 (trace A), all of which are form A except for sample 43, which also contains a small amount of form B. The diffractograms are offset in the y-axis direction for comparison purposes.

[0080] [Figure 48]Figure 48 shows a graphical representation of Run 48, showing temperature (Curve B) and turbidity (Curve A) as a function of time. The markers on Curve C represent the seeding points.

[0081] [Figure 49] Figure 49 shows a graphical representation of runs 50 and 51, showing temperature (curve A) and turbidity (curve C for run 50 and curve B for run 51) as a function of time. The markers on the x-axis represent the seeding points.

[0082] [Figure 50] Figure 50 shows a graphical representation of experiment 53, showing temperature (curve D), moisture content (curve A), counts for chord lengths 100-1000 μm (curve E), counts for chord lengths 10-100 μm (curve B), and counts for chord lengths <10 μm (curve C) as a function of time. Data recording began when the reaction vessel was already at 60°C.

[0083] [Figure 51] Figure 51 shows a graphical representation of the data from experiment 53 collected with a Particle Track G400 probe, showing the number of counts for chord lengths between 100 and 1000 μm (curve C), the number of counts for chord lengths between 10 and 100 μm (curve A), the number of counts for chord lengths <10 μm (curve B) and its mean square (curve D) as a function of time.

[0084] [Figure 52] FIG. 52 shows the XRPD pattern of sample 53.

[0085] [Diagram 53] Figure 53 shows an overlay of XRPD patterns of samples, from bottom to top: sample 53 (trace C), 42 (trace B, crystalline form A), and 10 (trace A, crystalline form B). The diffractograms are offset in the y-axis direction for comparison purposes.

[0086] [Figure 54]FIG. 54 shows optical microscope images from sample 53, the neat powder (left) and the powder suspended in paraffin oil (right).

[0087] [Figure 55] FIG. 55 shows the TG-FTIR thermogram performed on sample 53.

[0088] [Figure 56] Figure 56 shows the proton nuclear magnetic resonance (1H-NMR) spectrum of sample 53 recorded in DMSO-d6. The peak at 3.3 ppm corresponds to water contained in the DMSO-d6 solvent, and the peak at 2.5 ppm corresponds to the DMSO-d6 solvent.

[0089] [Figure 57] Figure 57 shows the H-NMR spectrum of the amorphous form of the compound of formula 1 recorded in DMSO-d6. The peak at 3.3 ppm corresponds to water contained in the DMSO-d6 solvent, and the peak at 2.5 ppm corresponds to the DMSO-d6 solvent.

[0090] [Figure 58] Figure 58 shows the high performance liquid chromatography (HPLC) results for sample 53, including the entire HPLC chromatogram (top), an enlarged view of the range corresponding to retention times of 5.9 to 7.1 minutes (middle), and a summary table of the detected peaks (bottom).

[0091] [Figure 59] Figure 59 shows a graphical representation of the data from experiment 54 collected with the EasyViewer probe, showing the particle counts in the in-focus image in the length range of 100-1000 μm (curve E), the particle counts in the in-focus image in the length range of 10-100 μm (curve C), the particle counts in the in-focus image in the length range of <10 μm (curve F), turbidity (curve B), temperature (dashed curve D), and dosage (dashed curve A) as a function of time.

[0092] [Figure 60]FIG. 60 shows the particles observed with the EasyViewer probe in experiment 54 after seeding with sample 46 (crystal form A).

[0093] [Figure 61] FIG. 61 shows particles observed with the EasyViewer probe in experiment 54 after the first cooling was started.

[0094] [Figure 62] FIG. 62 shows the particles observed with the EasyViewer probe at the end of experiment 54 at 20° C.

[0095] [Figure 63] Figure 63 shows the XRPD pattern of Sample 54 (crystalline form A).

[0096] [Figure 64] Figure 64 shows an overlay of XRPD patterns of samples, from bottom to top: Samples 54 (trace C), 42 (trace B, crystalline form A), and 10 (trace A, crystalline form B). The diffractograms are offset in the y-axis direction for comparison purposes.

[0097] [Figure 65] FIG. 65 shows optical microscope images from Sample 54, the neat powder (left) and the powder suspended in paraffin oil (right).

[0098] [Figure 66] FIG. 66 shows the TG-FTIR thermogram performed on sample 54.

[0099] [Figure 67] Figure 67 shows the H-NMR spectrum of sample 54 recorded in DMSO-d6. The peak at 3.3 ppm corresponds to water contained in the DMSO-d6 solvent, and the peak at 2.5 ppm corresponds to the DMSO-d6 solvent.

[0100] [Figure 68] Figure 68 shows the HPLC results for sample 54, including the entire HPLC chromatogram (top), an enlarged view of the range corresponding to retention times of 5.9 to 7.1 minutes (middle), and a summary table of the detected peaks (bottom).

[0101] [Figure 69] Figure 69 shows the XRPD pattern of Sample 55 (crystalline form C).

[0102] [Figure 70] Figure 70 shows an overlay of XRPD patterns of samples, from bottom to top: Sample 2 (trace A, crystalline form A), 10 (trace B, crystalline form B), and 55 (trace C, crystalline form C). The diffractograms are offset in the y-axis direction for comparison purposes.

[0103] [Figure 71] FIG. 71 shows the DSC curve of sample 55 of crystalline form C.

[0104] [Figure 72] Figure 72 shows scanning electron microscope (SEM) images of sample 55. The magnifications are 100x on the left and 250x on the right.

[0105] [Figure 73] Figure 73 shows SEM images of sample 55. The magnification is 500x on the left and 1000x on the right.

[0106] [Figure 74] Figure 74 shows SEM images of sample 55. The magnifications are 3000x on the left and 9000x on the right.

[0107] [Figure 75]Figure 75 shows an overlay of XRPD patterns of the samples, which are, from bottom to top, sample 63 (trace D), 63A (trace C), 42 (trace B, crystalline form A), and 55 (trace A, crystalline form C). The diffractograms are offset in the y-axis direction for comparison purposes. The arrow points to the reflection of crystalline form A.

[0108] [Figure 76] Figure 76 shows an overlay of XRPD patterns of the samples, which are, from bottom to top, sample 64 (trace E), 64A (trace D), 64B (trace C), 42 (trace B, crystalline form A), and 55 (trace A, crystalline form C). The diffractograms are offset in the y-axis direction for comparison purposes. The arrow points to the reflection of crystalline form A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0109] The present invention will be described in more detail below. Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention pertains.

[0110] The contents of all publications cited as references are incorporated herein by reference in their entirety.

[0111] Descriptions and embodiments disclosed in one part of the present invention may be applied to other descriptions and embodiments in other parts of the present invention. That is, all combinations of the various elements disclosed in the present invention are within the scope of the present invention. Moreover, the scope of the present invention should not be limited by the specific descriptions set forth below in this specification.

[0112] Additionally, although preferred methods or samples are described herein, similar or equivalent thereto are within the scope of the present invention. Additionally, the term "comprising" is intended to have an open-ended meaning, permitting the inclusion of additional elements not specified.

[0113] Unless otherwise indicated, all numbers expressing amounts of ingredients or characteristics, such as molecular weight, reaction conditions, etc., used in the specification and claims should be understood in all cases as modified by the term "about". Thus, unless otherwise indicated, the numerical characteristics described in the following specification and claims are approximations that may vary depending on the desired characteristics sought to be obtained in embodiments of the invention. As used herein, the term "about" means within 5%, more preferably within 1% to 2%, of a particular value or range. For example, "about 10%" refers to 9.5% to 10.5%, preferably 9.8% to 10.2%. In another example, "about 100°C" refers to 95°C to 105°C, preferably 98°C to 102°C.

[0114] Unless otherwise indicated, all XRPD measurements in this disclosure are taken using a monochromator at Cu-Kα1 (on a STOE STADI P) at a wavelength of 1.5405958 Å. Exceptions include Samples 37-40 and 56-60 described herein, and Samples 42 and 55 after solubility testing also described herein, which were measured using a D8 Advance (Bruker ASX, Germany) analyzer at Cu-Kα at a wavelength of 1.5405958 Å.

[0115] It will be apparent to those skilled in the art that, unless otherwise specified, the peak values ​​from powder X-ray diffraction studies reported herein are subject to experimental error typically observable in the field. Specifically, the peaks are interpreted as lying within an angular variation of ±0.5° of the values ​​reported herein. Preferably, the peaks are interpreted as lying within an angular variation of ±0.2° of the values ​​reported herein, and more preferably, as lying within an angular variation of ±0.1°.

[0116] The S-enantiomer is believed to be more active than the R-enantiomer, and therefore is preferred.

[0117] Amorphous Form of the Compound of Formula 1 The characteristics of the amorphous forms of the compound of Formula 1 disclosed herein, as well as those in US '365 and WO '188, are described below.

[0118] The X-ray powder diffraction (XRPD) of the amorphous form of the compound of formula 1 is shown in FIG.

[0119] When subjected to differential scanning calorimetry ("DSC"), the amorphous form of a sample of the compound of Formula 1 had a ΔC p The step showed a glass transition at 59° C. (see FIG. 3).

[0120] Amorphous samples of the compound of formula 1 contain residual amounts of isopropanol, but may have a weight loss of about 0.9% corresponding to isopropanol in thermogravimetric analysis (TG-FTIR) at temperatures up to about 200° C., and may decompose above 280° C. (see FIG. 2).

[0121] Hygroscopicity studies (by dynamic moisture sorption and desorption, or DVS) show that the amorphous form of the compound of formula 1 is slightly hygroscopic, absorbing approximately 1.5% water after five hours of storage at 95% relative humidity (see Figures 4 and 5). No crystallization occurs during DVS testing of the amorphous form of the compound of formula 1, and the amorphous form is quite kinetically stable (see Figure 6).

[0122] Crystalline forms of the compound of formula 1 Form A In one aspect of the disclosure, there is provided a crystalline form of the compound of formula 1, characterized in that the crystalline form exhibits an XRPD pattern including peaks at diffraction angles 2θ of 18.1°, 19.5°, and 22.3° ±0.2°, hereinafter referred to as crystalline form A.

[0123] In one embodiment, crystalline form A may exhibit an XRPD pattern comprising peaks at three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, preferably four or more, of 2θ values ​​±0.2° selected from the group consisting of 3.5°, 7.1°, 8.9°, 9.1°, 9.6°, 10.7°, 12.6°, 14.0°, 16.9°, 18.1°, 18.4°, 18.9°, 19.5°, 20.1°, 21.0°, 22.0°, 22.3°, and 22.7°.

[0124] In another embodiment, crystalline form A may exhibit an XRPD pattern that includes peaks at three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, preferably four or more, of 2θ values ​​±0.2° selected from the group consisting of 3.53°, 7.10°, 8.94°, 9.12°, 9.63°, 10.68°, 12.63°, 13.95°, 16.86°, 18.06°, 18.39°, 18.90°, 19.48°, 20.10°, 21.00°, 22.00°, 22.26°, and 22.71°.

[0125] In particular, crystalline form A may exhibit an XRPD pattern including peaks at 2θ values ​​of 3.5°, 7.1°, 8.9°, 9.1°, 9.6°, 10.7°, 18.1°, 18.4°, 18.9°, 19.5°, 20.1°, 21.0°, 22.0°, 22.3°, and 22.7° ±0.2°.

[0126] More specifically, crystalline form A may exhibit an XRPD pattern including peaks at 2θ values ​​of 3.5°, 7.1°, 8.9°, 9.1°, 9.6°, 10.7°, 12.6°, 14.0°, 16.9°, 18.1°, 18.4°, 18.9°, 19.5°, 20.1°, 21.0°, 22.0°, 22.3°, and 22.7° ±0.2° (see Figure 13).

[0127] Form A may have an exothermic peak in differential scanning calorimetry (DSC, 10° C. / min) with an onset of about 132° C. and a maximum of about 136° C. Form A may have an exothermic peak in DSC (10° C. / min) at about 135.5±4° C. (See FIG. 15).

[0128] Form A may lose about 0.50% or less in weight at temperatures up to about 180° C. and may decompose at or above 280° C. in thermogravimetric analysis (TG-FTIR). In one embodiment, Form A may lose about 0.45% or less, about 0.40% or less, about 0.35% or less, about 0.30% or less, about 0.25% or less, about 0.20% or less, or about 0.15% or less in weight at temperatures up to about 180° C. (See FIG. 10).

[0129] In another embodiment of the present invention, crystalline form A of the compound of formula 1 may be in substantially pure form.

[0130] In one embodiment, the crystalline form A of the compound of formula 1 may have a purity of 95% or greater in crystalline form.

[0131] In one embodiment, crystalline form A of the compound of formula 1 may exhibit peak intensities corresponding to the angles and d-spacing in Å set forth in Table 1 below. [Table 1] TIFF2024522715000004.tif232159

[0132] Crystalline form A of the compound of formula 1 has been found to have unexpectedly and significantly improved (i.e., reduced) hygroscopicity, and crystalline form A is more stable than crystalline form B (see Examples 27a and 27b).

[0133] Crystalline form A of the compound of formula 1 is an anhydrous form containing traces of residual water. Hygroscopicity tests (by DVS) show that crystalline form A is slightly hygroscopic, absorbing approximately 0.5% water after five hours of storage at 95% relative humidity (see Figures 16 and 17). In contrast, crystalline form B of the compound of formula 1 absorbed a maximum of 1.2% water after five hours of storage at 95% relative humidity (see Figures 22 and 23). (The amorphous form of the compound of formula 1 absorbed approximately 1.5% water after five hours of storage at 95% relative humidity, see Figures 4 and 5.)

[0134] As shown in the present disclosure, crystalline form A of the compound of formula 1 exhibited up to 98.7 area % (as determined by HPLC) (see Example 241).

[0135] According to the results of competitive slurry experiments (see Example 27a), crystalline form A of the compound of formula 1 is more stable than crystalline form B of the same compound over the temperature range of 25° C. to 75° C. Since the melting temperature and melting enthalpy of crystalline form A are higher than those of crystalline form B, crystalline form A is the stable form (at least over the range of 25° C. to 75° C.) and the two crystalline forms are monotropic.

[0136] Concerning crystalline form C, crystalline form A is a stable form at room temperature, whereas crystalline form C is a stable form above 30 degrees (see Example 5b).

[0137] Crystal form B In one embodiment of the present disclosure, there is provided a crystalline form of the compound of formula 1, characterized in that it exhibits an X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2θ of 3.5°, 19.2°, and 22.3° ±0.2°, hereinafter referred to as crystalline form B (see FIG. 19).

[0138] In one embodiment, crystalline form B may exhibit an XRPD pattern comprising peaks at 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, preferably 4 or more, of 2θ that is a value of ±0.2° selected from the group consisting of 3.5°, 7.1°, 9.1°, 9.4°, 9.8°, 10.6°, 11.1°, 13.5°, 17.7°, 18.0°, 18.6°, 18.9°, 19.2°, 19.5°, 19.8°, 20.3°, 21.0°, 21.5°, 22.3°, and 22.7°.

[0139] In another embodiment, crystalline form B may exhibit an XRPD pattern comprising peaks at 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, preferably 4 or more, of 2θ values ​​±0.2° selected from the group consisting of 3.50°, 7.05°, 9.12°, 9.42°, 9.82°, 10.59°, 11.08°, 13.45°, 17.65°, 18.04°, 18.56°, 18.94°, 19.17°, 19.45°, 19.80°, 20.28°, 20.99°, 21.47°, 22.26°, and 22.69°.

[0140] In particular, crystalline form B may exhibit an XRPD pattern including peaks at 2θ values ​​that are ±0.2° of 3.5°, 7.1°, 9.1°, 9.4°, 9.8°, 11.1°, 13.5°, 17.7°, 18.0°, 19.2°, 19.8°, 21.5°, 22.3°, and 22.7°.

[0141] More particularly, crystalline form B may exhibit an XRPD pattern including peaks at 2θ that are ±0.2° values ​​of 3.5°, 7.1°, 9.1°, 9.4°, 9.8°, 10.6°, 11.1°, 13.5°, 17.7°, 18.0°, 18.6°, 18.9°, 19.2°, 19.5°, 19.8°, 20.3°, 21.0°, 21.5°, 22.3°, and 22.7°.

[0142] Crystalline form B may have a differential scanning calorimetry (DSC, 10° C. / min) exotherm peak with an onset of about 124° C. and a maximum of about 133° C. Crystalline form B may have a DSC (10° C. / min) exotherm peak at about 132.6±4° C. (See FIG. 20 and FIG. 21.)

[0143] Crystalline form B may lose about 1.0% or less weight in thermogravimetric analysis (TG-FTIR) at temperatures up to about 250° C. and may decompose at or above 280° C. In one embodiment, crystalline form B may lose about 0.95% or less, about 0.90% or less, about 0.85% or less, or about 0.80% or less weight at temperatures up to about 250° C. (See FIG. 11).

[0144] In another embodiment of the present invention, crystalline form B of the compound of formula 1 may be in substantially pure form.

[0145] In one embodiment, the crystalline form B of the compound of formula 1 may have a purity of 95% or greater in crystalline form.

[0146] In one embodiment, crystalline form B of the compound of formula 1 may exhibit peak intensities corresponding to the angles and d-spacing in Å set forth in Table 2 below. [Table 2] TIFF2024522715000006.tif129164

[0147] Crystal form C In one embodiment of the disclosure, there is provided a crystalline form of the compound of formula 1, characterized in that it exhibits an X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2θ of 4.6°, 20.5°, and 21.7° ±0.2°, hereinafter referred to as crystalline form C (see Figure 69).

[0148] In one embodiment, crystalline form C may exhibit an XRPD pattern comprising peaks at 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, preferably 4 or more, at 2θ values ​​of ±0.2° selected from the group consisting of 4.6°, 7.6°, 12.4°, 13.8°, 18.0°, 18.4°, 20.0°, 20.5°, and 21.7°.

[0149] In another embodiment, crystalline form C may exhibit an XRPD pattern comprising peaks at 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, preferably 4 or more, at 2θ values ​​±0.2° selected from the group consisting of 4.58°, 7.56°, 12.44°, 13.79°, 17.98°, 18.42°, 19.92°, 20.54°, and 21.69°.

[0150] In particular, crystalline form C may exhibit an XRPD pattern including peaks at ±0.2° values ​​2θ of 4.6°, 12.4°, 18.0°, 18.4°, 20.0°, 20.5°, and 21.7°.

[0151] More particularly, crystalline form C may exhibit an XRPD pattern including peaks at ±0.2° values ​​2θ of 4.6°, 7.6°, 12.4°, 13.8°, 18.0°, 18.4°, 20.0°, 20.5°, and 21.7°.

[0152] Form C may have a differential scanning calorimetry (DSC, 10° C. / min) exotherm with an onset of about 140° C. and a maximum of about 143° C. Form C may have a DSC (10° C. / min) exotherm at about 142.8±4° C. (See FIG. 71).

[0153] In another embodiment of the present invention, crystalline form C of the compound of formula 1 may be in substantially pure form.

[0154] In one embodiment, the crystalline form C of the compound of formula 1 may have a purity of 95% or greater in crystalline form.

[0155] In one embodiment, crystalline form C of the compound of formula 1 may exhibit peak intensities and d-spacing in Å corresponding to the angles set forth in Table 3 below. [Table 3] TIFF2024522715000008.tif139163

[0156] For crystalline forms A, B, and C of the compound of formula 1, XRPD patterns can be obtained, for example, using a D8 Advance (Bruker ASX, Germany) analyzer when illuminated with a Cu-Kα source, or, for example, using a STOE STADI P analyzer equipped with a Mythen 1K detector when illuminated with a CuKα1 source. The Cu-Kα (D8 Advance, Bruker) or Cu-Kα1 (STOE STADI P) source can have a wavelength of 1.5406 Å.

[0157] These peaks have a relative intensity (I / I o In one embodiment, the peaks can have a relative intensity (I / I) of about 10% or more, about 11% or more, about 12% or more, about 13% or more, about 14% or more, about 15% or more, about 16% or more, about 17% or more, about 18% or more, about 19% or more, about 20% or more, about 21% or more, about 22% or more, about 23% or more, about 24% or more, about 25% or more, about 26% or more, about 27% or more, about 28% or more, about 29% or more, about 30% or more, about 31% or more, about 32% or more, about 33% or more, about 34% or more, about 35% or more, about 36% or more, about 37% or more, about 38% or more, about 37% or more, or about 40% or more. o ) may be a peak having

[0158] As used herein, the term "substantially pure" means at least 95% purity, preferably 97% purity, or more preferably 99% purity, where 95% purity means that other crystalline forms (other crystalline forms, amorphous forms, etc.) of the compound of Formula 1 are present at 5% or less, 97% purity means that other crystalline forms (other crystalline forms, amorphous forms, etc.) are present at 3% or less, and 99% purity means that other crystalline forms (other crystalline forms, amorphous forms, etc.) of the compound of Formula 1 are present at 1% or less.

[0159] Method for Preparing Crystalline Form A of Compound of Formula 1 Another aspect of the present invention provides a method for preparing crystalline form A of the compound of formula 1.

[0160] In one embodiment, the method comprises:

[0161] Dissolving a compound of formula 1 in one or more components A, optionally with stirring and / or heating; [ka] The compound of Formula 1 may be in an amorphous form, one or more crystalline forms, or a combination thereof, and component A is an organic solvent suitable for dissolving the compound of Formula 1, non-limiting examples of which include C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, n-heptane, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBM. and preferred non-limiting examples of component A include one or more of C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine.

[0162] Optionally, one or more components B are added, which are poor solvents that reduce the solubility of the mixture. Non-limiting examples of component B include water and C5-C 12 of cyclic or acyclic hydrocarbon alkanes (e.g., cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably one or more of water and heptane, and filtering the resulting solid.

[0163] In another embodiment, the method comprises:

[0164] Dissolving a compound of formula 1 in one or more components A, optionally with stirring and / or heating; [ka] The compound of Formula 1 may be in an amorphous form, one or more crystalline forms, or a combination thereof, and component A is an organic solvent suitable for dissolving the compound of Formula 1, non-limiting examples of which include C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, n-heptane, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME. , THF, toluene, and triethylamine, and preferred non-limiting examples of component A include one or more of C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine;

[0165] Optionally, adding one or more components B, which are poor solvents that reduce the solubility of the mixture. Non-limiting examples of component B include water and C5-C 12 adding a cyclic or acyclic hydrocarbon alkane (e.g., cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably one or more of water and heptane;

[0166] Optionally, distilling off one or more components A and, if present, one or more components B;

[0167] and filtering, washing, and drying the solids.

[0168] In another embodiment, the method comprises:

[0169] dissolving a compound of formula 1 in one or more components A with stirring and / or heating; [ka] The compound of Formula 1 may be in an amorphous form, one or more crystalline forms, or a combination thereof, and component A is an organic solvent suitable for dissolving the compound of Formula 1, non-limiting examples of which include C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, n-heptane, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME. , THF, toluene, and triethylamine, and preferred non-limiting examples of component A include one or more of C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine;

[0170] Optionally, adding one or more components B, which are poor solvents that reduce the solubility of the mixture. Non-limiting examples of component B include water and C5-C 12 adding a cyclic or acyclic hydrocarbon alkane (e.g., cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably one or more of water and heptane;

[0171] Optionally, distilling off one or more components A;

[0172] Seeding the suspension with the already prepared crystalline form A of compound of formula 1;

[0173] Optionally, adding one or more components B, which are poor solvents that reduce the solubility of the mixture. Non-limiting examples of component B include water and C5-C 12adding a cyclic or acyclic hydrocarbon alkane (e.g., cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably one or more of water and heptane; Cooling the mixture; and subjecting the mixture to temperature cycling; agitating the mixture; and filtering, washing, and drying the solids.

[0174] In one embodiment for large scale preparation of crystalline form A of compound of formula 1, [ka] The method is: (a) dissolving a compound of formula 1 in, optionally, 50-100 mL, optionally 70 mL, of ethyl acetate to form a solution; (b) heating the solution from (a) to 50-75°C, optionally to 60°C, at about 1 K / min; (c) adding 200-400 mL, optionally 280 mL, of heptane at 2 mL / min at 50-75° C., optionally 60° C.; (d) seeding the resulting fine suspension with the already prepared crystalline form A of the compound of formula 1 (about 0.1% by weight) at 50-75°C, optionally at 60°C; (e) cooling to 15-25°C, optionally to 20°C, at about 2K / h; (f) temperature cycling at 15-25°C, optionally at 20°C, waiting for 1 hour, heating to 35-45°C, optionally at 40°C at about 15K / h, then cooling to 15-25°C, optionally at 20°C at about 5K / h, and repeating 2-5 times, optionally 3 times; (g) stirring at 15-25° C., optionally at 20° C., for about 1 day; (h) filtering through a fritted glass (porosity 4) and washing with 30 mL of a mixture of ethyl acetate / heptane (1:4), optionally with 30 mL; (i) drying the filter cake on the filter, optionally for about 2 hours, optionally with reduced pressure; (j) drying the recovered powder overnight at <5 mbar and room temperature.

[0175] In yet another embodiment for large scale preparation of crystalline form A of compound of formula 1, [ka] The method is: (a) dissolving a compound of formula 1 in isopropanol, optionally in an amount of 60-100 mL, optionally 80 mL, to form a solution; (b) heating the solution from (a) to 50-75°C, optionally to 60°C, at about 1 K / min; (c) adding 100-200 mL, optionally 160 mL, of water at 50-75° C., optionally 60° C., at 1 mL / min; (d) seeding the resulting fine suspension with the already prepared crystalline form A of the compound of formula 1 (about 0.1% by weight) at 50-75°C, optionally at 60°C; (e) cooling to 15-25°C, optionally to 20°C, at about 2K / h; (f) temperature cycling at 15-25°C, optionally at 20°C, waiting for 1 hour, heating to 35-45°C, optionally at 40°C at about 15K / h, then cooling to 15-25°C, optionally at 20°C at about 5K / h, and repeating 2-5 times, optionally 3 times; (g) stirring at 15-25° C., optionally at 20° C., for about 1 day; (h) filtering through a fritted glass (porosity 4) and washing with 30 mL of an isopropanol / water (1:2) mixture, optionally with 30 mL; (i) drying the filter cake on the filter, optionally for about 2 hours, optionally with reduced pressure; (j) drying the recovered powder overnight at <5 mbar and room temperature.

[0176] Method for Preparing Crystalline Form B of Compound of Formula 1 Another aspect of the present invention provides a method for preparing crystalline form B of the compound of formula 1.

[0177] In one embodiment, the method comprises: Dissolving a compound of formula 1 in one or more components A, optionally with stirring and / or heating; [ka] Component A is an organic solvent suitable for dissolving the compound of Formula 1, non-limiting examples of which include C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, n-heptane, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triglycerides. and ethylamine. Preferred non-limiting examples of component A include one or more of C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine.

[0178] Optionally, one or more components B are added, which are poor solvents that reduce the solubility of the mixture. Non-limiting examples of component B include water and C5-C 12 cyclic or acyclic hydrocarbon alkanes (e.g., cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably water and one or more of heptane;

[0179] distilling off one or more components A and, if present, one or more components B; and filtering the resulting suspension.

[0180] In another embodiment, the method comprises: Dissolving the compound of formula 1 in component A, optionally with stirring and / or heating; [ka]

[0181] The compound of Formula 1 may be in an amorphous form, one or more crystalline forms, or a combination thereof, and component A is an organic solvent suitable for dissolving the compound of Formula 1, non-limiting examples of which include C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, n-heptane, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TB and dissolving the component A in an aqueous solution containing tertiary amine such as ethyl acetate, tetrahydrofuran, ethyl acetate, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine. Preferred non-limiting examples of component A include one or more of C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine.

[0182] Adding one or more components B, where the component B is a poor solvent that reduces the solubility of the mixture. Non-limiting examples of the component B include water and C5-C 12adding a cyclic or acyclic hydrocarbon alkane (e.g., cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably one or more of water and heptane;

[0183] The method includes the steps of distilling off one or more components A and one or more components B, and filtering the resulting suspension.

[0184] Method for Preparing Crystalline Form C of Compound of Formula 1 Another aspect of the present invention provides a method for preparing crystalline form C of the compound of formula 1.

[0185] In one embodiment, the method comprises dissolving a compound of formula 1 in one or more components A, optionally with stirring and / or heating; [ka] the compound of formula 1 dissolved in the dissolving step is in amorphous form, one or more crystalline forms, or a combination thereof; and component A is an organic solvent suitable for dissolving the compound of formula 1, non-limiting examples of which include C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, n-heptane, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine; Preferred, non-limiting examples of component A include one or more of C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, ethyl lactate, isopropyl acetate, isobutyl acetate, methyl ethyl ketone (MEK), methanol, medium chain triglycerides (e.g., MIGLYOL® 812), N-methyl-2-pyrrolidone (NMP), 1-octanol, 1-propanol, 2-propanol, methyl tert-butyl ether (TBME), tetrahydrofuran (THF), toluene, and triethylamine.

[0186] Adding one or more components B, which are poor solvents that reduce the solubility of the mixture. Non-limiting examples of component B include water and C5-C 12 of cyclic or acyclic hydrocarbon alkanes (e.g., cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably one or more of water and heptane, and filtering the resulting solid.

[0187] In another embodiment, the method comprises dissolving a compound of formula 1 in one or more components A at a temperature of about 50-70° C., optionally about 60° C., optionally with stirring; [ka] the compound of formula 1 dissolved in the dissolving step is in amorphous form, one or more crystalline forms, or a combination thereof; and component A is an organic solvent suitable for dissolving the compound of formula 1, non-limiting examples of which include C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, n-heptane, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine; Preferred, non-limiting examples of component A include one or more of C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, ethyl lactate, isopropyl acetate, isobutyl acetate, methyl ethyl ketone (MEK), methanol, medium chain triglycerides (e.g., MIGLYOL® 812), N-methyl-2-pyrrolidone (NMP), 1-octanol, 1-propanol, 2-propanol, methyl tert-butyl ether (TBME), tetrahydrofuran (THF), toluene, and triethylamine.

[0188] Optionally, one or more components B are added, which are poor solvents that reduce the solubility of the mixture. Non-limiting examples of component B include water and C5-C 12 adding a cyclic or acyclic hydrocarbon alkane (e.g., cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably one or more of water and heptane;

[0189] cooling the solution formed from the dissolving and optional adding steps to about 35-60°C, optionally to about 50°C;

[0190] The cooled solution is optionally concentrated, optionally evaporated, filtered and dried.

[0191] In another embodiment, the method comprises: (a) dissolving a compound of formula 1 in a mixture of one or more components A and one or more components B at a temperature of about 50-70°C, optionally about 60°C, optionally with stirring, wherein the compound of formula 1 dissolved in the dissolving step is in amorphous form, in one or more crystalline forms, or a combination thereof;

[0192] Component A is an organic solvent suitable for dissolving the amorphous form of the compound of formula 1, non-limiting examples of which include C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, n-heptane, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine, optionally ethyl acetate;

[0193] Component B is a poor solvent that reduces the solubility of the mixture. Non-limiting examples of component B include water and C5-C 12 a cyclic or acyclic hydrocarbon alkane (e.g., cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably heptane; (b) stirring until a suspension is formed; (c) cooling the solution formed by dissolving the compound of formula 1 in component A and component B to about 35-60°C, optionally to about 45°C; (d) distilling off one or more components A and one or more components B, optionally under a nitrogen stream; (e) adding additional component B, optionally heptane, and stirring; (f) distilling off one or more components A and one or more components B, optionally with a nitrogen stream, optionally with a weak nitrogen stream, at a temperature of about 35-60°C, optionally about 45°C; (g) filtering the suspension through a fritted glass (porosity); (h) drying the filter, optionally under reduced pressure.

[0194] In one embodiment, when component B is added by any of the methods described above or any of the methods of the present disclosure, the volume ratio (v / v) of component A to component B can optionally be in the range of about 20:1 to about 1:20. In one embodiment, the volume ratio (v / v) of component A to component B is in the range of about 10:1 to about 1:10, about 8:1 to about 1:8, about 5:1 to about 1:5, about 3:1 to about 1:3, about 2:1 to about 1:2. In one embodiment, the volume ratio (v / v) of component A to component B is about 3:1, about 2:1, about 1:1, about 4:5, about 1:3, about 1:10.

[0195] In the dissolving step of any of the methods of the present disclosure, the compound of formula 1, which may be amorphous and / or crystalline, may be dissolved in one or more solvents selected from the group consisting of C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, and triethylamine. The solvent may be, for example, a single solvent such as methanol, ethanol, isopropyl alcohol, acetone, ethyl acetate, isopropyl acetate, and methyl t-butyl ether, or a mixture thereof, for example, a mixture of methanol and methyl t-butyl ether.

[0196] The compound of formula 1 may be prepared according to the methods disclosed in US '365 and WO '188, the disclosures of which are incorporated herein by reference in their entireties, however, the embodiments described herein are not so limited, and amorphous forms of the compound of formula 1 may be prepared using any method known to one of ordinary skill in the relevant art.

[0197] The washing and drying steps are not particularly limited. Washing can be carried out using the solvent used in the dissolving step. Drying can be carried out by any method that does not affect the stability of the crystalline form of the compound of formula 1, for example, at a temperature of about 40°C to about 50°C for about 15 hours to 30 hours.

[0198] If solvents other than those mentioned above are used for crystallization, other crystal forms may be obtained.

[0199] Pharmaceutical Uses and Pharmaceutical Compositions In another aspect of the present invention, there is provided a pharmaceutical composition comprising as an active ingredient one or more crystalline forms of the compound of formula 1 and at least one pharma- ceutically acceptable carrier or excipient. In another aspect, the one or more crystalline forms of the compound of formula 1 are selected from the group consisting of crystalline forms A, B, and C of the compound of formula 1.

[0200] As disclosed in US '365 and WO '188, the compounds of formula 1 have an EC of <1 ppm when evaluated in vitro for anti-flea (Ctenocephalides felis (cat flea)) activity by ingestion. 50 The same document also discloses that the compound of formula 1 has a half-life of 50 days.

[0201] One or more crystalline forms of the compound of formula 1 or pharmaceutical compositions thereof can be used to treat and / or control pests. The term "pests" includes ectoparasites and endoparasites on and in animals and in the field of hygiene. Particular pests are fleas, ticks, mites, flies, worms, and lice. Even more particular pests are fleas, flies, mites, and mites.

[0202] Animals in the context of the present invention are understood to include vertebrates. The term vertebrates in this context is understood to include mammals, including fish, amphibians, reptiles, birds, and humans. One preferred group of vertebrates according to the present invention includes livestock animals, such as cows, horses, pigs, sheep, and goats, poultry, such as chickens, turkeys, guinea fowl, and geese, fur animals, such as minks, foxes, chinchillas, rabbits, and warm-blooded animals, including companion animals, such as ferrets, guinea pigs, rats, hamsters, cats, and dogs, and humans. A further preferred group of vertebrates according to the present invention includes fish, including salmon. Particularly preferred animals are cats and dogs.

[0203] In the context of the present invention, ectoparasites are understood to be in particular insects, acarids (mites and ticks) and crustaceans (sea lice). These include insects of the following orders: Lepidoptera, Coleoptera, Homoptera, Hemiptera, Heteroptera, Diptera, Dictyoptera, Thysanoptera, Orthoptera, Anoplura, Siphonaptera, Mallophaga, Thysanura, Isoptera, Psocoptera and Hymenoptera. However, ectoparasites which may be mentioned in particular are those which annoy humans or animals and which carry pathogens, such as the house fly Musca domestica, the Australian house fly Musca vetustissima, the European house fly Musca autumnalis, the little house fly Fannia canicularis, the flesh fly Sarcophaga carnaria, the sheep blow fly Lucilia cuprina, the broad-banded blow fly Lucilia sericata, the cow fly Hypoderma bovis, the cow fly Hypoderma lineatum, the flies of the genus Chrysomyia chloropyga, the human dung fly Dermatobia hominis, the screwworm fly Cochliomyia hominivorax, the horse fly Gasterophilus intestinalis, flies such as the sheep fly (Oestrus ovis), stable flies such as the horn fly (Haematobia irritans), a subspecies of the horn fly (Haematobia irritans exigua), and the stable fly (Stomoxys calcitrans), horse flies (hors flies) such as the various species of the genus Haematopota (Haematopota spp.) (e.g. Haematopota pluvialis) and the subfamilies Tabanidae (e.g. Tabanus spp.) (e.g. Tabanus nigrovittatus) as well as the subfamilies Chrysops spp.bot flies, including subfamilies such as the Chrysopsinae (e.g. the deer fly Chrysops caecutiens), Hippoboscid flies, e.g. Melophagus ovinus (sheep ked), tsetse flies, e.g. Glossinia spp., midges, e.g. Ceratopogonidae (biting midges), Simuliidae (black flies), Psychodidae (sand flies), as well as other biting insects such as Anopheles spp., Aedes spp. and Culex spp. blood-sucking insects, such as mosquitoes, e.g. Ctenocephalides felis and Ctenocephalides canis (cat and dog fleas), Xenopsylla cheopis, Pulex irritans, Ceratophyllus gallinae, fleas, e.g. Dermatophilus penetrans, e.g. Linognathus spp, Haematopinus spp, Solenopotes spp, Pediculus spp, Lice (order Anoplura) such as blood-sucking lice (Anoplura) such as Bovicola (Damalinia) ovis, Bovicola (Damalinia) bovis and other Bovicola species, as well as lice (order Mallophaga) such as Bovicola (Damalinia) ovis, Bovicola (Damalinia) bovis and other Bovicola species. Ectoparasites are also included, for example mites (e.g. Chorioptes bovis, Cheyletiella spp., Dermanyssus gallinae, Ortnithonyssus spp.Representative ticks include members of the order Acarina, such as Demodex canis, Sarcoptes scabiei, Psoroptes ovis and Psorergates spp., and ticks. Representative ticks include the genera Boophilus, Amblyomma, and Vexillaria, which preferably infest vertebrates, including warm-blooded animals, including livestock, such as cattle, horses, pigs, sheep and goats, poultry, such as chickens, turkeys, guinea fowl and geese, fur animals, such as mink, fox, chinchilla, rabbits, and companion animals, such as ferrets, guinea pigs, rats, hamsters, cats and dogs, as well as humans and fish. a), Anocentor, Dermacentor, Haemaphysalis, Hyalomma, Ixodes, Rhipicentor, Margaropus, Rhipicephalus, Argas, Otobius and Ornithodoros.

[0204] The crystalline forms of the compound of formula 1 are also active against all or individual developmental stages of animal pests that show normal sensitivity as well as resistance to widely used parasiticides. This is particularly true for resistant insects and members of the order Acarina. The insecticidal, ovicidal and / or acaricidal effect of the active substances of the invention can manifest itself directly, i.e. by killing the pests or destroying their eggs, either immediately or after some time has passed, for example when molting occurs, or indirectly, for example by reducing the number of laid eggs and / or the hatching rate, with a good efficacy corresponding to a killing rate (mortality rate) of at least 50-60%.

[0205] The crystalline forms of the compound of formula 1 may also be used against hygiene pests, particularly those of the orders Diptera, Orthoptera, Dictyoptera (e.g. Blattidae (cockroaches), e.g. Blatella germanica, Blatta orientalis, Periplaneta americana) of the families Muscidae, Sarcophagidae, Anophilidae, and Culicidae, and those of the orders Hymenoptera (e.g. Formicidae (ants) and Vespidae (wasps).

[0206] The crystalline forms of the compound of formula (I) are also effective against ectoparasites of fish, particularly the subclass of Copepoda (e.g., Siphonostomatoida (sea lice)), whilst being well tolerated by fish.

[0207] The crystalline forms of the compound of formula 1 may also be used against worms of the class Cestoda, including the subclasses Eucestoda and Cestodaria.

[0208] The crystalline forms of the compound of formula 1 also have sustainable efficacy against plant parasitic mites and insect parasites. In the case of Acarina spider mites, they are effective against eggs, nymphs, and adults of the family Tetranychidae (Tetranychus spp. and Panonychus spp.).

[0209] The crystalline form of the compound of formula 1 has high activity against sap-sucking insects of the suborder Homoptera, in particular pests of the families Aphididae, Delphacidae, Cicadellidae, Psyllidae, Loccidae, Diaspididae and Eriophydidae (e.g. citrus rust mites), pests of the orders Hemiptera, Heteroptera and Thysanoptera, and herbivorous insects of the orders Lepidoptera, Coleoptera, Diptera and Orthoptera.

[0210] The crystalline forms of the compounds of formula 1 are likewise suitable as soil pesticides against harmful organisms in the soil.

[0211] Thus, the crystalline forms of the compound of formula 1 are effective against all developmental stages of sap-sucking and crop-feeding insects in crops such as, for example, cereals, cotton, rice, corn, soybeans, potatoes, vegetables, fruits, tobacco, hops, citrus, avocado, and other crops.

[0212] The crystalline forms of the compound of formula 1 are also effective against plant parasitic nematodes such as species of the genera Meloidogyne, Heterodera, Pratylenchus, Ditylenchus, Radopholus, and Rizoglyphus.

[0213] The crystalline form of the compound of formula 1 is effective against helminths. Helminths are commercially important because they cause severe diseases in mammals and poultry, such as sheep, pigs, goats, cattle, horses, donkeys, camels, dogs, cats, rabbits, guinea pigs, hamsters, chickens, turkeys, guinea fowl, and other domestic birds, as well as exotic birds. Typical nematodes include Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostonum, Oesophagostonum, Charbertia, Trichuris, Strongylus, and the like. ), Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris. The trematodes include in particular the Fasciolideae, in particular Fasciola hepatica.

[0214] The insecticidal action of the crystalline form of the compound of formula 1 according to the invention corresponds to a mortality rate of about 50-60% of the pests mentioned, more preferably a mortality rate of more than 90%, most preferably 95-100%. The crystalline form of the compound of formula (I) is preferably used internally and externally in raw form or, preferably, together with adjuvants conventionally used in the technical field of formulations and can thus be processed in known manner to give, for example, liquid formulations (e.g., spot-ons, pour-ons, spray-ons, emulsions, suspensions, solutions, emulsifiable concentrates, solution concentrates), semisolid formulations (e.g., creams, ointments, pastes, gels, liposomal preparations) and solid preparations (e.g., capsules, powders including soluble powders, food additive tablets including granules, etc., or embedding the active ingredient in polymeric substances such as implants or microparticles). As with the compositions, the application method is selected depending on the intended purpose and the prevailing situation.

[0215] The crystalline form of the compound of formula 1 can be administered alone or in the form of a composition.In practice, the compound of the present invention is usually administered in the form of a composition, i.e., in admixture with at least one acceptable excipient.The proportion and nature of any acceptable excipient is determined by the properties of the selected compound of the present invention, the selected route of administration, and the standard practice in the veterinary and pharmaceutical fields.

[0216] In one embodiment, the present invention provides a composition comprising one or more crystalline forms of the compound of formula 1 and at least one acceptable excipient.

[0217] To achieve such treatment and / or eradication, the crystalline form of the compound of formula 1 can be administered in any form and route that makes the compound bioavailable.The crystalline form of the compound of formula 1 can be administered by various routes, including oral, particularly by tablets and capsules.The crystalline form of the compound of formula 1 can be administered more specifically by parenteral route, including inhalation, subcutaneous, intramuscular, intravenous, intraarterial, transdermal, intranasal, rectal, vaginal, intraocular, topical, sublingual, and buccal, intraperitoneal, intraadiposally, intrathecal, and via local delivery, for example, by catheter or stent.

[0218] Those skilled in the art can easily select the appropriate form and administration route according to the specific characteristics of the selected crystalline form, the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances.The pharmaceutical composition of the present invention can be administered to a subject in the form of, for example, tablets, including chewable tablets, capsules, cachets, papers, lozenges, oblates, elixirs, boli, ointments, transdermal patches, aerosols, inhalants, suppositories, solutions, solutions, injections, and suspensions.

[0219] The term "acceptable excipient" refers to those excipients typically used in the preparation of veterinary and pharmaceutical compositions, and should be pure and non-toxic in the amount used. They are generally solid, semi-solid, or liquid substances that can function as a vehicle or medium for the active ingredient in the aggregate. Some examples of acceptable excipients are identified in Remington's Pharmaceutical Sciences and Handbook of Pharmaceutical Excipients and include diluents, vehicles, carriers, ointment bases, binders, disintegrants, lubricants, glidants, sweeteners, flavorings, gel bases, sustained release matrices, stabilizers, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coatings, and others.

[0220] In one embodiment, the composition is adapted for oral administration, such as a tablet or capsule, or a liquid formulation adapted for oral administration, such as a solution or suspension. In one embodiment, the composition is adapted for oral administration, such as a chewable formulation adapted for oral administration. In yet another embodiment, the composition is a liquid or semi-solid formulation, such as a solution or suspension or paste, adapted for parenteral administration.

[0221] In one embodiment, the composition is adapted for injectable administration, such as a solution or suspension adapted for injectable administration.

[0222] Particular compositions for use in a subject in the treatment and / or control of pests, preferably ectoparasites, include solutions, injections, typical emulsions, e.g., water-free organic compositions, preferably oil-based compositions, that form emulsions with bodily fluids when added to the subject's body, emulsions including microemulsions and self-emulsifying compositions, suspensions (water solutions), pour-on formulations, food additives, powders, tablets including effervescent tablets, boli, capsules including microcapsules, and chewable treats. Particularly preferred composition forms are tablets, capsules, food additives, or chewable treats.

[0223] The compositions of the present invention are prepared in a manner well known in the veterinary and pharmaceutical arts and contain at least one crystalline form of the compound of formula 1 as an active ingredient. The amount of the crystalline form of compound 1 of formula 1 may vary depending on its particular form, and may conveniently be 1% to about 50%, preferably about 10% to about 35%, more preferably about 15% to about 25% of the weight of the unit dosage form. The pharmaceutical compositions are preferably formulated in unit dosage form form, with each dose typically containing about 0.5 mg to about 100 mg of the crystalline form of the present invention. One or more unit dosage forms may be incorporated to affect the therapeutic dosage. Others may be present in any other form of the compound of formula 1 (other possible crystalline forms, amorphous forms, etc.).

[0224] In one embodiment, the present invention also provides a method for treating a pest, the method comprising administering to a subject in need thereof an effective amount of a crystalline form of the compound of formula 1, the method optionally further comprising an effective amount of at least one additional active compound or co-crystal.

[0225] In one embodiment, the present invention also provides a method for controlling a pest, the method comprising administering to a subject in need thereof an effective amount of a crystalline form of the compound of formula 1, the method optionally further comprising an effective amount of at least one additional active compound or co-crystal.

[0226] In one embodiment, the invention also provides a method for treating or controlling a pest, the method comprising contacting an environment of a subject with an effective amount of a crystalline form of the compound of Formula 1, the method optionally further comprising an effective amount of at least one additional active compound or co-crystal.

[0227] Thus, the present invention provides for the use of a crystalline form of the present invention as a medicament, including the manufacture of a medicament. In one embodiment, the present invention provides for the manufacture of a medicament comprising a crystalline form of the compound of formula 1 for treating a pest. In one embodiment, the present invention provides for the manufacture of a medicament comprising a crystalline form of the compound of formula 1 for combating a pest.

[0228] The terms "treating," "to treat," "treated," or "treatment" include, but are not limited to, inhibiting, slowing, halting, reducing, ameliorating, reversing the progression or severity of existing symptoms, or preventing a disorder, condition, or disease. For example, an adult heartworm infection would be treated by administering a compound of the invention. Treatment may be applied or administered therapeutically.

[0229] The terms "control", "controlling" or "controlled" refer to, but are not limited to, lowering, reducing or ameliorating the risk of a symptom, disorder, condition or disease, and protecting an animal from a symptom, disorder, condition or disease. Controlling can refer to therapeutic, prophylactic or preventative administration. For example, larvae or immature pests may be asymptomatic, but are controlled by acting on the larvae or immature pests to prevent the infection from progressing to a symptomatic or debilitating infection by mature pests.

[0230] Thus, the use of the crystalline forms of the present invention to treat and / or control pests, particularly ectoparasites, refers to the use of the crystalline forms of the present invention to affect various forms of pests throughout their life cycle, regardless of whether the subject is symptomatic, including diseased or mortal, and regardless of the stage of challenge.

[0231] As used herein, "administering to a subject" includes, but is not limited to, administration to the skin, subcutaneously, intramuscularly, mucosally, submucosally, transdermally, orally, or intranasally. Administration can include injection or local administration, such as pour-on or spot-on administration. The pour-on or spot-on method is particularly advantageous for use with herd animals, such as cattle, horses, sheep, or pigs, where it is difficult or time-consuming to treat all animals orally or by injection. Due to its simplicity, this method can of course also be used with all other animals, including individual livestock or pet animals, and is highly favored by animal breeders, as it can often be performed without the presence of a veterinary specialist.

[0232] The terms "subject" and "patient" refer to vertebrates as described herein, including humans and non-human mammals and fish, such as dogs, cats, mice, rats, guinea pigs, rabbits, ferrets, cows, horses, sheep, goats, and pigs. Particular subjects are pet or companion animals that are mammals, such as dogs and cats, as well as mice, guinea pigs, ferrets, and rabbits.

[0233] The term "effective amount" refers to an amount that provides the desired benefit to a subject, and includes both therapeutic and curative administrations. The amount will vary from subject to subject and will depend on several factors, including the subject's overall physical condition and the severity of the underlying cause of the condition being treated, concurrent treatments, and the amount of the crystalline form of the compound of formula 1 used to maintain the desired response at a beneficial level.

[0234] An effective amount can be readily determined by the attending physician as one of ordinary skill in the art by using known techniques and by observing results obtained under similar circumstances. In determining an effective amount, dosage, many factors are considered by the attending physician, including, but not limited to, the species of the patient, the patient's size, age, and overall health, the particular condition, disorder, infection or disease involved, the degree of severity of the condition, disorder or disease involved, the response of the individual patient, the particular crystalline form administered, the mode of administration, the bioavailability characteristics of the administered preparation, the administration regimen selected, the use of concomitant medications, and other relevant circumstances. An effective amount, therapeutic dosage of the present invention is expected to be in the range of 0.5 mg to 100 mg. The specific amount can be determined by one of ordinary skill in the art. These dosages are based on subjects weighing about 1 kg to about 20 kg, although a diagnostician can determine appropriate dosages for subjects weighing outside this weight range. An effective amount, therapeutic dosage of the present invention is expected to be in the range of 0.1 mg to 10 mg / kg for a subject. Dosage regimens are expected to be monthly, quarterly, semi-annually, or annually.

[0235] The crystalline forms of the compound of Formula 1 may be combined with one or more other active compounds, co-crystals, or therapies for the treatment of one or more disorders, diseases, or conditions, including treating pests for which it is indicated. The crystalline forms of the compound of Formula 1 may be administered simultaneously, sequentially, or separately in combination with one or more compounds, co-crystals, or therapies for treating pests and other disorders.

[0236] It is therefore understood that the compositions and methods of the invention optionally include an effective amount of at least one additional active compound and / or co-crystal. Additional active compounds useful in the present invention include those used to treat fleas, ticks, flies, and mosquitoes, and include macrocyclic lactones such as milbemycin oxime, imidacloprid, spinosad, pyriproxyfen, premethrin, S-methoprene, praziquantel, and moxidectin. Further exemplary additional active compounds include, but are not limited to, afoxolaner, broflanilide, fluralaner, fluxamethamide, isocycloceram, lotilaner, modoflaner, nicofluprole, sarolaner, tigolaner, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, parabendazole, thiabendazole, triclabendazole, amitraz, demiditraz, clorsulon, closantel, oxyclonazide, lafoxanide, cyphenothrin, deltamethrin, flumethrin, permethrin, cyromazine, delucan, ter, diamphenetide, dicyclanil, dinotefuran, imidacloprid, nitenpyram, thiamethoxam, abamectin, doramectin, emamectin, eprinomectin, ivermectin, moxidectin, selamectin, milbemycin oxime, emodepside, epsiprantel, fipronil, fluazuron, fluhexafon, indoxacarb, levamisole, lufenuron, metaflumizone, methoprene, monepantel, morantel, niclosamide, nitroscanate, nitroxynil, novaluron, oxantel, praziquantel, pyrantel, pyriprole, pyriproxyfen, sisapronil, spinosad, spinetoram and triflumezopyrim, or a salt of any of the foregoing.

[0237] The activity of the compounds of the present invention may be determined by a variety of methods, including in vitro and in vivo methods.

[0238] When administered to a patient, the total daily dosage of the crystalline form of the compound of formula 1 may vary depending on the route of administration, the time of administration, the type of other compounds in combination, or the patient's age, sex, weight, condition, medical history, etc. Thus, the dosage of the compound may be determined within a range in which a desired therapeutic effect is achieved without causing any harmful or serious adverse effects.

[0239] The pharmaceutical composition may be in an oral or parenteral dosage form.

[0240] In the case of oral dosage forms, the carriers used may include sweeteners, binders, dispersants, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, disinfectants, lubricants, fillers, flavorings, coating agents, etc. For example, the carriers may include lactose, calcium hydrogen phosphate, hydroxypropylcellulose, carboxymethylcellulose, colloidal silicon dioxide, fumed silica, magnesium stearate, talc, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, Opadry White, etc.

[0241] Examples of available injectable carriers include distilled water, physiological saline, glucose solution, pseudo-glucose solution, alcohol, glycol ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, surfactant, suspending agent, emulsifying agent, etc.

[0242] As such, the above description of pharmaceutical compositions according to embodiments of the present invention may be applied to the details of methods for treating and / or controlling pests.

[0243] The dose used in the method for treating and / or controlling pests may be a therapeutically and / or controlling effective amount. The above description of the dose of the pharmaceutical composition may be applied to the method for treating and / or controlling pests as such.

[0244] The statements concerning the pharmaceutical uses and pharmaceutical compositions of the compounds of formula 1 disclosed in US '365 and WO '188 may be applied to the crystalline forms of the compounds of formula 1 according to the invention.

[0245] In one aspect, in any of the above embodiments, the crystalline form of the compound of formula 1 is (a) may be selected from the group consisting of crystalline forms A, B, and C of the compound of formula 1; (b) the compound of formula 1 may be in crystalline form A; (c) the compound of formula 1 may be in crystalline form B; (d) the compound of formula 1 may be in crystalline form C; (e) The compound of formula 1 may be in crystalline forms A and B, (f) The compound of formula 1 may be in crystalline forms A and C; (g) The compound of formula 1 may be in crystalline forms B and C, (h) The compound of formula 1 may be in the crystalline forms A, B and C. The present invention will now be described in more detail with reference to the following examples, which are for illustrative purposes only and are not intended to limit the present invention.

[0246] Analytical device and measuring method 1. X-ray Powder Diffraction (XRPD)

[0247] X-ray powder diffraction (XRPD) analysis of the samples was performed using a STOE Stadi P diffractometer equipped with a MYTHEN1K analyzer or a D8 Advance (Bruker ASX, Germany) analyzer in the 2θ range of 1.500° to 50.480°. For the STOE Stadi P equipped with a Mythen1K detector, samples (~10 mg to ~20 mg of powder) were measured between two acetate or Kapton films. For the D8 Advance analyzer, samples were measured in a silicon single crystal sample holder with a depth of 0.5 mm.

[0248] No special treatment was used in the preparation of the samples other than the application of slight pressure to distribute the powder over the surface area to be irradiated. Ambient air atmosphere was used for all measurements, and each sample was rotated during the measurement.

[0249] The measurements were performed as follows: Anode material (Kα): STOE Stadi P diffractometer with D8 Advance analyzer at Cu-Kα (1.540598 Å) or MYTHEN1K analyzer at Cu-Kα1 (1.540598 Å) Scan range: 1.5°~50.5° Generator settings: 40mA, 40.0kV Scan speed: 12 seconds / step Temperature: room temperature Step size: 0.02° 2θ

[0250] 2. Differential Scanning Calorimetry (DSC)

[0251] Differential scanning calorimetry (DSC) analysis was performed on samples hermetically sealed in closed gold or aluminum pans under ambient conditions using a Q2000 (TA Instruments) at a heating rate of 10° C. / min in the temperature range of −50° C. to 250° C. Melting points are taken as peak maximums.

[0252] 3.Thermogravimetric analysis (TG-FTIR)

[0253] Thermogravimetric analysis (TG-FTIR) was performed in an aluminum sample pan with a pinhole in a N2 atmosphere using a Netzsch Thermo-Microbalance TG209 coupled to a Bruker FT-IR spectrometer Vector 22 at a heating rate of 10 °C / min within the temperature range of 20 °C to 360 °C.

[0254] 4. Dynamic Ventilation (DVS)

[0255] Adsorption and desorption isotherms were obtained using an SPS11-100n Sorptions Prufsystem from ProUmid (formerly Projekt Messtechnik). Approximately 5 mg to approximately 20 mg of sample was placed in an aluminum sample plan on a microbalance and equilibrated at 50% relative humidity (RH) before starting the following applied measurement program. A humidity change rate of 5% per hour was used. The applied measurement program can be written as follows: (1) 50% RH for 2 hours (2) 50→0% RH (5% / hour), 5 hours at 0% RH (3) 0→95% RH (5% / hour), 5 hours at 95% RH (4) 95→0% RH (5% / hour), 5 hours at 0% RH (5) 0→95% RH (5% / hour), 5 hours at 95% RH (6) 95→50% RH (5% / hour), 2 hours at 50% RH.

[0256] Once the isotherm was completed, the sample was collected and reanalyzed by XRPD.

[0257] 4. Hygroscopicity Classification

[0258] Hygroscopicity was classified based on the mass gain at 85% relative humidity (RH) compared to the initial mass as follows: deliquescent (enough water was adsorbed to become liquid), very hygroscopic (≥15% mass gain), hygroscopic (<15% but ≥2% mass gain), slightly hygroscopic (<2% but ≥0.2% mass gain), or nonhygroscopic (<0.2% mass gain).

[0259] 5. 1 H-NMR analysis

[0260] 1 H-NMR analyses were carried out using a Bruker DPX300 spectrometer. 1 H NMR spectra were recorded using a proton frequency of 300.13 MHz, a 30° excitation pulse, a 1 s recycle delay, an accumulation of 16 scans, and deuterated DMSO as the solvent. Chemical shifts were referenced relative to TMS at 0 ppm. The peak at 2.5 ppm corresponds to the solvent peak of DMSO.

[0261] Non-limiting embodiments of the present disclosure are described below. Embodiment 1. A crystalline form of the compound of formula 1, [ka] A crystalline form characterized by exhibiting an X-ray powder diffraction (XRPD) pattern containing peaks at 2θ values ​​of 18.1°, 19.5°, and 22.3° ±0.2°.

[0262] Embodiment 2. 2. The crystalline form of embodiment 1, wherein the XRPD pattern further comprises peaks at one or more 2θ values ​​of ±0.2° selected from the group consisting of 3.5°, 7.1°, 8.9°, 9.1°, 9.6°, 10.7°, 12.6°, 14.0°, 16.9°, 18.4°, 18.9°, 20.1°, 21.0°, 22.0°, and 22.7°.

[0263] Embodiment 3. 2. The crystalline form of embodiment 1, wherein the XRPD pattern further comprises peaks at two or more of 2θ values ​​±0.2° selected from the group consisting of 3.5°, 7.1°, 8.9°, 9.1°, 9.6°, 10.7°, 12.6°, 14.0°, 16.9°, 18.4°, 18.9°, 20.1°, 21.0°, 22.0°, and 22.7°.

[0264] Embodiment 4. 2. The crystalline form of embodiment 1, wherein the XRPD pattern further comprises peaks at three or more of 2θ values ​​±0.2° selected from the group consisting of 3.5°, 7.1°, 8.9°, 9.1°, 9.6°, 10.7°, 12.6°, 14.0°, 16.9°, 18.4°, 18.9°, 20.1°, 21.0°, 22.0°, and 22.7°.

[0265] Embodiment 5. 2. The crystalline form of embodiment 1, wherein the XRPD pattern further comprises peaks at four or more 2θ values ​​of ±0.2° selected from the group consisting of 3.5°, 7.1°, 8.9°, 9.1°, 9.6°, 10.7°, 12.6°, 14.0°, 16.9°, 18.4°, 18.9°, 20.1°, 21.0°, 22.0°, and 22.7°.

[0266] Embodiment 6. 2. The crystalline form of embodiment 1, wherein the XRPD pattern further comprises peaks at five or more 2θ values ​​of ±0.2° selected from the group consisting of 3.5°, 7.1°, 8.9°, 9.1°, 9.6°, 10.7°, 12.6°, 14.0°, 16.9°, 18.4°, 18.9°, 20.1°, 21.0°, 22.0°, and 22.7°.

[0267] Embodiment 7. 2. The crystalline form of embodiment 1, wherein the XRPD pattern further comprises peaks at six or more 2θ values ​​of ±0.2° selected from the group consisting of 3.5°, 7.1°, 8.9°, 9.1°, 9.6°, 10.7°, 12.6°, 14.0°, 16.9°, 18.4°, 18.9°, 20.1°, 21.0°, 22.0°, and 22.7°.

[0268] Embodiment 8. The peak has a relative intensity (I / I o 2. The crystalline form of embodiment 1, having the formula:

[0269] EMBODIMENT 9. The crystalline form of embodiment 1, wherein the peaks are measured by XRPD using an X-ray wavelength of 1.5406 Å.

[0270] EMBODIMENT 10. The crystalline form of any one of the preceding embodiments, wherein each 2θ value of said peak has an angular variation of ±0.1°.

[0271] Embodiment 11. The crystalline form of any one of the preceding embodiments, wherein the DSC exotherm peak is at a temperature of about 135.5±4° C.

[0272] Embodiment 12. The crystalline form of any one of the preceding embodiments, wherein the crystalline form has a weight loss of 0.4% or less at up to about 180° C. in a thermogravimetric analysis (TG-FTIR).

[0273] Embodiment 13. The crystalline form of any one of embodiments 1-9, wherein the crystalline form is substantially pure.

[0274] Embodiment 14. The crystalline form of embodiment 1, wherein the crystalline form is at least 95% pure.

[0275] EMBODIMENT 15. A pharmaceutical composition comprising the crystalline form according to any one of embodiments 1 to 14 as an active ingredient and at least one pharma- ceutically acceptable carrier or diluent.

[0276] EMBODIMENT 16. The pharmaceutical composition of embodiment 15, wherein the crystalline form constitutes 80% or more of the total amount of the compound of Formula 1 in the pharmaceutical composition.

[0277] EMBODIMENT 17. The pharmaceutical composition according to embodiment 15, wherein the pharmaceutical composition is for the treatment of pests in animals, optionally cats and / or dogs.

[0278] EMBODIMENT 18. The pharmaceutical composition of embodiment 15, wherein the pests include ticks and / or fleas.

[0279] EMBODIMENT 19. A method for preparing the crystalline form according to any one of embodiments 1 to 14, comprising the steps of:

[0280] Dissolving the compound of formula 1 in one or more components A, optionally with stirring and / or heating, wherein the compound of formula 1 dissolved in the dissolving step is in amorphous form, one or more crystalline forms, or a combination thereof, and component A is an organic solvent suitable for dissolving the compound of formula 1, preferably C1-C4 alcohol, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, n-heptane, isobutyl acetate, MEK, methanol, medium chain triethanolamine, ethyl acetate ... dissolving the glyceride, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine, more preferably one or more of C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine;

[0281] Optionally, adding one or more components B, which are poor solvents that reduce the solubility of the mixture, and which are selected from water and C5-C 12 and adding to the mixture a cyclic or acyclic hydrocarbon alkane (e.g., cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably comprising one or more of water and heptane.

[0282] EMBODIMENT 20. A method for preparing the crystalline form according to any one of embodiments 1 to 14, comprising the steps of:

[0283] Dissolving the compound of formula 1 in one or more components A, optionally with stirring and / or heating, wherein the compound of formula 1 dissolved in the dissolving step is in amorphous form, one or more crystalline forms, or a combination thereof, and component A is an organic solvent suitable for dissolving the compound of formula 1, preferably C1-C4 alcohol, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, n-heptane, isobutyl acetate, MEK, methanol, medium chain triglyceride, glycerol ... and dissolving the glyceride in an aqueous medium such as a C1-C4 alcohol, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine, more preferably one or more of C1-C4 alcohol, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine.

[0284] Adding one or more components B, where the components B are poor solvents that reduce the solubility of the mixture, and the components B are water and C5-C 12 cyclic or acyclic hydrocarbon alkanes (e.g., cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably including one or more of water and heptane;

[0285] and filtering, washing, and drying the resulting solid.

[0286] EMBODIMENT 21. 21. A crystalline form of the compound of formula 1 prepared by the method of embodiment 19 or 20.

[0287] EMBODIMENT 22. A crystalline form of the compound of formula 1, [ka] A crystalline form characterized by exhibiting an X-ray powder diffraction (XRPD) pattern containing peaks at 2θ values ​​of 4.6°, 20.5°, and 21.7° ±0.2°.

[0288] EMBODIMENT 23. 23. The crystalline form of embodiment 22, wherein the XRPD pattern further comprises peaks at one or more 2θ values ​​of ±0.2° selected from the group consisting of 7.6°, 12.4°, 13.8°, 18.0°, 18.4°, and 20.0°.

[0289] EMBODIMENT 24. 23. The crystalline form of embodiment 22, wherein the XRPD pattern further comprises peaks at two or more of 2θ values ​​±0.2° selected from the group consisting of 7.6°, 12.4°, 13.8°, 18.0°, 18.4°, and 20.0°.

[0290] EMBODIMENT 25. 23. The crystalline form of embodiment 22, wherein the XRPD pattern further comprises peaks at three or more of 2θ values ​​that are ±0.2° selected from the group consisting of 7.6°, 12.4°, 13.8°, 18.0°, 18.4°, and 20.0°.

[0291] 26. 23. The crystalline form of embodiment 22, wherein the XRPD pattern further comprises peaks at four or more 2θ values ​​of ±0.2° selected from the group consisting of 7.6°, 12.4°, 13.8°, 18.0°, 18.4°, and 20.0°.

[0292] EMBODIMENT 27. 23. The crystalline form of embodiment 22, wherein the XRPD pattern further comprises peaks at five or more 2θ values ​​of ±0.2° selected from the group consisting of 7.6°, 12.4°, 13.8°, 18.0°, 18.4°, and 20.0°.

[0293] 28. 23. The crystalline form of embodiment 22, wherein the XRPD pattern further comprises peaks at values ​​2θ of 7.6°, 12.4°, 13.8°, 18.0°, 18.4°, and 20.0° ±0.2°.

[0294] 29. The peak has a relative intensity (I / I o 23. The crystalline form of embodiment 22, having the formula:

[0295] EMBODIMENT 30. The crystalline form of embodiment 22, wherein the peaks are measured by XRPD using an X-ray wavelength of 1.5406 Å.

[0296] EMBODIMENT 31. The crystalline form of any one of embodiments 22 to 30, wherein each 2θ value of said peak has an angular variation of ±0.1°.

[0297] EMBODIMENT 32. The crystalline form of any one of embodiments 22 to 30, wherein the DSC exotherm peak is at a temperature of about 142.8±4° C.

[0298] EMBODIMENT 33. The crystalline form of any one of embodiments 22-30, wherein the crystalline form is substantially pure.

[0299] EMBODIMENT 34. The crystalline form of embodiment 22, wherein the crystalline form is at least 95% pure.

[0300] EMBODIMENT 35. A pharmaceutical composition comprising a crystalline form according to any one of embodiments 22 to 34 as an active ingredient and at least one pharma- ceutically acceptable carrier or diluent.

[0301] EMBODIMENT 36. The pharmaceutical composition of embodiment 15 or 35, wherein the crystalline form constitutes 80% or more of the total amount of the compound of Formula 1 in the pharmaceutical composition.

[0302] 37. The pharmaceutical composition according to embodiment 15 or 35, wherein the pharmaceutical composition is for the treatment of pests in animals, optionally cats and / or dogs.

[0303] 38. The pharmaceutical composition according to embodiment 15 or 35, wherein the pests comprise ticks and / or fleas.

[0304] 39. A method for preparing a crystalline form according to any one of embodiments 22 to 34, comprising the steps of:

[0305] Dissolving the compound of formula 1 in one or more components A, optionally with stirring and / or heating, wherein the compound of formula 1 dissolved in the dissolving step is in amorphous form, one or more crystalline forms, or a combination thereof, and component A is an organic solvent suitable for dissolving the compound of formula 1, preferably C1-C4 alcohol, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, n-heptane, isobutyl acetate, MEK, methanol, medium chain triethanolamine, ethyl acetate ... dissolving the glyceride, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine, more preferably one or more of C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine;

[0306] Adding one or more components B, where the components B are poor solvents that reduce the solubility of the mixture, and the components B are water and C5-C 12 cyclic or acyclic hydrocarbon alkanes (e.g., cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably including one or more of water and heptane;

[0307] Distilling off one or more components A and one or more components B;

[0308] and filtering the resulting solid.

[0309] EMBODIMENT 40. A method for preparing a crystalline form according to any one of embodiments 22 to 34, comprising the steps of:

[0310] Dissolving the compound of formula 1 in one or more components A, wherein the compound of formula 1 dissolved in the dissolving step is in amorphous form, one or more crystalline forms, or a combination thereof, and component A is an organic solvent suitable for dissolving the compound of formula 1, preferably C1-C4 alcohol, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, heptane, n-heptane, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octyl alcohol, ethyl acetate, ethyl acrylate, ethyl acetate ... and dissolving the ethanol in an isopropanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine, more preferably one or more of C1-C4 alcohols, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine.

[0311] Adding one or more components B, wherein the components B are water and C5-C 12 cyclic or acyclic hydrocarbon alkanes (e.g., cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably including one or more of water and heptane;

[0312] agitating the solution formed from the dissolving step;

[0313] distilling off one or more components A and one or more components B from the solution;

[0314] adding one or more additional components B;

[0315] distilling off one or more components A and one or more components B from a solution containing one or more additional components B.

[0316] EMBODIMENT 41. 41. A crystalline form of the compound of formula 1 prepared by the method of embodiment 39 or 40. EXAMPLES

[0317] Preparation Example: Preparation of Compounds of Formula 1 The compound of formula 1, 2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide, was prepared according to the process described below.

[0318] A mixture of methyl 4-bromo-2-methyl-benzoate (10.0 g, 42.3 mmol), N,N,N',N'-tetramethylethylenediamine (3.96 mL, 26.3 mmol), palladium(II) acetate (0.5 g, 2.12 mmol), butyldi-1-adamantylphosphine (2 g, 5.29 mmol), and toluene (65 mL) was charged to a pressure vessel. The reaction was pressurized with CO gas (approximately 414 kPa) and heated to 85° C. overnight. The reaction was cooled to room temperature. The reaction mixture was filtered through Celite®, washed with toluene, and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography on silica gel (0-10% ethyl acetate in cyclohexane) to give methyl 4-formyl-2-methyl-benzoate. LC-MS (Method A)R t = 0.95 min (no ionization).

[0319] A mixture of methyl 4-formyl-2-methyl-benzoate (2.05 g, 11.2 mmol) in MeOH (65 mL) and aqueous NaOH (2 M, 65 mL) was stirred at room temperature for 5 h. The reaction mixture was acidified with concentrated HCl to pH ∼1. The reaction was diluted with ethyl acetate, the organic layer was separated, and the aqueous layer was washed with ethyl acetate. The organic layers were then combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 4-formyl-2-methyl-benzoic acid. LC-MS (Method B)R t = 0.71 min, m / z = 163.0 [MH]-.

[0320] To a suspension of 4-formyl-2-methyl-benzoic acid (1.8 g, 10.4 mmol) and oxalyl chloride (995 μL, 11.5 mmol) in DCM (35 mL) at room temperature under a N2 atmosphere was added DMF (25 μL). The reaction was stirred at room temperature for 3 h. The reaction mixture was concentrated to give the crude acid chloride. A solution of 2-amino-N-(2,2,2-trifluoroethyl)acetamide·HCl (2.25 g, 11.5 mmol) and NEt3 (3.2 mL, 23 mmol) in DCM (35 mL) was added to the crude acid chloride at 0 °C, then the reaction was allowed to warm to room temperature and stirred for 30 min. The reaction was diluted with DCM / water, the organic layer was collected and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% MeOH in DCM) to give 4-formyl-2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]benzamide. LC-MS (Method A) R t =0.69 min, m / z=303.0[M+H] + .

[0321] A solution of NHOH (32.6 M in water, 385 μL, 6.28 mmol) was added to 4-formyl-2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]benzamide (1.00 g, 3.14 mmol) in MeOH (15 mL) and the reaction was stirred at room temperature for 6 h. The solvent was removed under reduced pressure to give 4-[(E and Z)-hydroxyiminomethyl]-2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]benzamide. LC-MS (Method B)R t = 0.68 min and 0.70 min, m / z = 318.0 [M+H] + .

[0322] To a solution of 4-[(E and Z)-hydroxyiminomethyl]-2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]benzamide (1.08 g, 3.16 mmol) in DMF (3.34 mL) was added N-chlorosuccinimide (548 mg, 4.10 mmol) and the reaction was heated to 40° C. in 15 min. The reaction was cooled to 0° C. and 1-chloro-2-fluoro-5-(trifluoromethyl)-3-[1-(trifluoromethyl)vinyl]benzene (1.03 g, 3.15 mmol) was added, followed by NEt3 (484 μL, 3.47 mmol). The reaction was stirred at room temperature. The reaction was diluted with ethyl acetate and brine. The organic layer was separated, washed with more brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-60% ethyl acetate in cyclohexane) to give the title compound and its R-enantiomer. LC-MS (Method A) t =1.38 min, m / z=608.0[M+H] + . 1 HNMR(CDCl3,400MHz)δ8.04(dd,J=2,6Hz,1H),7.81(dd,J=2,6Hz,1H),7.47-7.56(m,3 H),6.90(brs,1H),6.71(brs,1H),4.18-4.23(m,3H),3.84-4.00(m,3H),2.48(s,3H).

[0323] The two enantiomers were separated by SFC on a Chiralpak® AS-H with column dimensions of 250 mm × 30 mm (5 μm) at a flow rate of 152 ml / min and a CO2-based mobile phase containing 10% MeOH containing 0.2% N,N-dimethylethylamine as an additive, to give the compound of formula 1 (2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S)-5-[3-chloro-2- Fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide), and its R-enantiomer, 2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5R)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide.

[0324] Preparation of Crystalline Form A of the Compound of Formula 1 Example 1: Preparation of crystalline form A of the compound of formula 1 At room temperature, 15 mL of 2:1 ethanol / water mixture was added to 5.0327 g of the compound of formula 1 after separation from its R-enantiomer in the preparative example (above). An orange paste formed around the magnetic stir bar. After stirring for 5 minutes, a suspension formed and the sticky material around the magnetic stir bar became solid. A spatula was used to break up the clumps and 15 mL of the solvent mixture was added. After two hours of stirring, a thick suspension was observed and 10 mL of the solvent system was added. No clumps were observed anymore. After stirring overnight at room temperature, the suspension was filtered on a fritted glass (porosity 4). The wet cake was white and the mother liquor was slightly orange. The mother liquor was used to rinse the reaction vessel. 10 mL of 2:1 ethanol / water mixture was used to wash the cake. The filter cake was dried on the filter for 10 minutes by applying vacuum and then transferred to a vessel (8.141 g) and further dried at room temperature under reduced pressure (<5 mbar). After drying overnight, 4.4091 g of material was recovered and submitted for XRPD analysis (see Figures 46, 47, 53, 64, 75, 76). Yield: 88%.

[0325] Crystalline Form A of Example 1 is referred to herein as Sample 42. An optical microscope image of Sample 42 is shown in FIG.

[0326] Example 2: Preparation of Crystalline Form A of the Compound of Formula 1 200 μL of ethanol / water 2:1 mixture was added to 90.2 mg of the amorphous form of the compound of formula 1. A solution was obtained with stirring at room temperature. After 5 min, precipitation was observed and stirring was no longer possible. An additional 600 μL of the solvent mixture was added and further stirring was carried out at room temperature. After stirring for three days, the resulting colorless suspension was filtered using a centrifugal unit filter (PVDF, 0.22 μm, 5 min, 5000 rpm). The vial was rinsed with mother liquor. The collected powder was subjected to XRPD. Crystalline form A of Example 2 is referred to herein as Sample 2 (see Figures 13 and 70).

[0327] Example 2a: Preparation of crystalline form A of the compound of formula 1 The remainder of sample 2 from example 2 was dried overnight at room temperature at 5 mbar. This dried sample is referred to herein as sample 2a. The XRPD pattern was unchanged and corresponded to crystalline form A of the compound of formula 1 (see Figures 18 and 29). Thermogravimetric analysis (TG-FTIR) showed a water loss of 0.13% from 25 to 180°C (see Figure 10). DSC analysis showed a melting point of 135.5°C with an onset of 132.7°C and a melting enthalpy of 65.6 J / g (see Figure 15). DVS analysis showed an uptake of 0.5% water at 95% relative humidity for 5 hours (see Figures 16 and 17). The XRPD pattern after DVS also corresponded to crystalline form A of the compound of formula 1 (see Figure 18).

[0328] Example 3: Preparation of crystalline form A of the compound of formula 1 200 μL of 2-propanol / water 3:1 mixture was added to 80.1 mg of the amorphous form of the compound of formula 1. A solution was obtained with stirring at room temperature. After 10 minutes, precipitation was observed. An additional 400 μL of the solvent mixture was added and further stirring was carried out at room temperature. After stirring for three days, the colorless suspension was filtered using a centrifugal unit filter (PVDF, 0.22 μm, 5 min, 5000 rpm). The vial was rinsed with mother liquor. The recovered powder was subjected to XRPD (see Figures 7 and 14). Crystalline Form A of Example 3 is referred to herein as Sample 3.

[0329] Example 4: Preparation of Crystalline Form A of the Compound of Formula 1 200 μL of ethyl acetate / heptane 1:1 mixture was added to 80.4 mg of the amorphous form of the compound of formula 1. A solution was obtained while stirring at room temperature. After three days, a solution was still observed. 500 μL of heptane was slowly added, forming a cloudy solution containing some sticky material. After 10 minutes, a suspension began to form. After 5 hours of stirring at room temperature, the suspension was filtered using a centrifugal unit filter (PVDF, 0.22 μm, 5 minutes, 5000 rpm). The vial was rinsed with mother liquor. The recovered powder was subjected to XRPD (see Figures 7 and 14). Crystalline Form A of Example 4 is referred to herein as Sample 4.

[0330] Example 5: Preparation of crystalline form A of the compound of formula 1 78.5 mg of the amorphous form of the compound of formula 1 was dissolved in 500 μL of acetonitrile at room temperature. 500 μL of water was added dropwise with stirring. After the addition, some "oil droplets" were observed in the solution. An additional 1 mL of water was added (acetonitrile and water 1:3), resulting in a cloudy solution with some oil droplets. Further stirring at room temperature. After stirring for three days, a colorless suspension was obtained and filtered using a centrifugal unit filter (PVDF, 0.22 μm, 5 min, 5000 rpm). The vial was rinsed with mother liquor. The recovered powder was subjected to XRPD (see Figures 7 and 14). Crystalline Form A of Example 5 is referred to herein as Sample 5.

[0331] Example 6: Preparation of crystalline form A of the compound of formula 1 91.1 mg of the amorphous form of the compound of formula 1 was dissolved in 500 μL of 1-propanol at room temperature. 500 μL of water was added dropwise while stirring. After addition, a cloudy solution was observed. An additional 1 mL of water was added (1-propanol and water 1:3), but no precipitation was observed. Stirring was continued at room temperature. After stirring for three days, a colorless suspension was obtained and filtered using a centrifugal unit filter (PVDF, 0.22 μm, 5 min, 5000 rpm). The vial was rinsed with mother liquor. The recovered powder was subjected to XRPD (see Figures 7 and 14). Crystalline Form A of Example 6 is referred to herein as Sample 6.

[0332] Example 7: Preparation of crystalline form A of the compound of formula 1 81.8 mg of the amorphous form of the compound of formula 1 was dissolved in 500 μL of TBME at room temperature. 500 μL of heptane was added dropwise while stirring. After the addition, a solution was still obtained, and another 500 μL of heptane was added, resulting in a cloudy solution. Another 500 μL of heptane was added, and a solution containing a sticky substance was formed, which was subjected to vortexing and ultrasonication for 2 minutes. No change was observed, and further stirring was performed at room temperature. After stirring for three days, a colorless suspension was obtained and filtered using a centrifugal unit filter (PVDF, 0.22 μm, 5 min, 5000 rpm). The vial was rinsed with mother liquor. The recovered powder was subjected to XRPD (see Figures 7 and 14). Crystalline Form A of Example 7 is referred to herein as Sample 7.

[0333] Example 8: Preparation of Crystalline Form B of the Compound of Formula 1 83.8 mg of the amorphous form of the compound of formula 1 was dissolved in 500 μL of MEK at room temperature. 500 μL of heptane was added dropwise while stirring. No precipitation was observed, and an additional 1 mL of heptane was added (MEK:heptane ratio 1:3). A solution was still obtained, and further stirring was carried out at room temperature. After three days of stirring, no precipitation was observed, so the vial was opened and the solvent was evaporated. After one day, 1 / 3 of the solvent was evaporated and precipitation was observed. The resulting suspension was filtered using a centrifugal unit filter (PVDF, 0.22 μm, 5 min, 5000 rpm). The vial was rinsed with mother liquor. The recovered powder was subjected to XRPD (see FIG. 8). Crystalline form B of Example 8 is referred to herein as Sample 8.

[0334] Example 9: Preparation of Crystalline Forms A and B of the Compound of Formula 1 92.9 mg of the amorphous form of the compound of formula 1 was dissolved in 500 μL of THF at room temperature. The vial was opened and the solvent was evaporated at room temperature. After three days, an oily residue was obtained. Further evaporation was performed under a stream of nitrogen at room temperature. After four days, the sample was still an oily residue. 400 μL of isobutyl acetate was added to the oily residue. After stirring, a solution was obtained at room temperature. 1.2 mL of heptane (stepwise in three portions of 400 μL) was slowly added, but no precipitation was observed. The solution was seeded with samples 6 and 10. The seeds did not dissolve. After stirring for 30 minutes, a suspension was obtained, half of which was filtered (centrifuge unit filter PVDF, 0.22 μm, 5 min, 5000 rpm). The recovered powder was designated sample 11a-1 and was subjected to XRPD (Kapton film). The remaining suspension was further stirred at room temperature. After stirring for three days, it was filtered using a centrifugal unit filter (PTFE, 0.22 μm, 5 min, 5000 rpm). The recovered powder was designated as sample 11a-2 and was subjected to XRPD (Kapton film) (see FIG. 7).

[0335] Example 10: Preparation of crystalline form A of the compound of formula 1 81.8 mg of the amorphous form of the compound of formula 1 was dissolved in 500 μL of acetonitrile at room temperature. The vial was opened and the solvent was evaporated at room temperature. After three days, an oily residue was obtained. Further evaporation was performed under a nitrogen stream at room temperature. After four days, the sample was still an oily residue. 400 μL of NMP was added to the oily residue. After stirring, a solution was obtained at room temperature. 800 μL of water (stepwise in two portions of 400 μL) was slowly added and precipitation was observed. A cloudy solution was formed around the stir bar with a sticky substance. After vortexing, a suspension could be obtained and filtered using a centrifugal unit filter (PTFE, 0.22 μm, 5 min, 5000 rpm). However, only a small amount of sticky substance was present on the filter. The mixture was collected and further stirred at room temperature. After stirring for three days, a suspension was obtained. Filtered using a centrifugal unit filter (PTFE, 0.22 μm, 5 min, 5000 rpm). The recovered powder was designated sample 12a and was subjected to XRPD (Kapton film) (see FIG. 7).

[0336] Example 11: Preparation of Crystalline Forms A+B of the Compound of Formula 1 74.6 mg of the amorphous form of the compound of formula 1 was suspended in 1 mL of water at 75° C. After stirring for 5 minutes, a sticky material formed around the stir bar. After stirring overnight, clumps were still observed around the stir bar and were scraped off with a spatula. After further stirring at 75° C. for 5 hours, the suspension was then filtered using a centrifugal unit filter (PVDF, 0.22 μm, 5 min, 5000 rpm). The vial was rinsed with mother liquor. The recovered powder was designated sample 13 and subjected to XRPD. The XRPD pattern corresponded to crystalline form A with some small additional reflections (2θ at 17.2°, 19.2°, and 21.5°) that could be assigned to crystalline form B. The remainder of sample 13 was dried overnight at room temperature at 5 mbar. This dried residue was designated sample 13a and subjected to XRPD, which showed no change from the XRPD pattern of sample 13. Thermogravimetric analysis (TG-FTIR) showed a water weight loss of 0.74% from 25 to 170 °C (see Figure 12).

[0337] Example 12: Preparation of crystalline form A of the compound of formula 1 83 mg of the amorphous form of the compound of formula 1 was suspended in 0.5 mL of a 1:1 mixture of ethanol / water at 75° C. After stirring for 5 minutes, an emulsion containing oil droplets was formed. After stirring overnight at 75° C., a suspension was formed and filtered using a centrifugal unit filter (PVDF, 0.22 μm, 5 min, 5000 rpm). The recovered powder was designated sample 14 and subjected to XRPD (see FIG. 14).

[0338] Example 13: Preparation of crystalline form A of the compound of formula 1 73.8 mg of the amorphous form of the compound of formula 1 was suspended in 0.5 mL of methanol / water 2:1 at 60° C. After stirring for 10 minutes, a fine suspension was observed. After stirring overnight at 60° C., a suspension was formed and filtered using a centrifugal unit filter (PVDF, 0.22 μm, 5 min, 5000 rpm). The recovered powder was designated sample 15 and subjected to XRPD (see FIG. 14).

[0339] Example 14: Preparation of crystalline form A of the compound of formula 1 39.8 mg of sample 5 and 58.7 mg of sample 6 were suspended in 1 mL of ethanol / water 1:9 mixture at room temperature. After vortexing and stirring for 10 min, it was seeded with sample 10. An additional 1 mL of the solvent mixture was added and further stirring was carried out at room temperature. After stirring for three days, the suspension was filtered using a centrifugal unit filter (PVDF, 0.22 μm, 5 min, 5000 rpm). The vial was rinsed with mother liquor. The recovered powder was designated sample 17 and was subjected to XRPD (see Figures 14 and 70).

[0340] Example 15: Preparation of crystalline form A of the compound of formula 1 85 mg of the amorphous form of the compound of formula 1 was suspended in 200 μL of 1:2 acetone / water mixture at room temperature. A sticky substance formed but did not dissolve completely. After vortexing, a cloudy solution was obtained. After two hours of stirring, a very concentrated suspension was formed and 1 mL of acetone / water mixture was added. After three days of stirring, the suspension was filtered using a centrifugal unit filter (PVDF, 0.22 μm, 5 min, 5000 rpm). The vial was rinsed with mother liquor. The recovered powder was designated sample 18 and subjected to XRPD, which corresponded to crystalline form A (Figure 14).

[0341] Example 16: Preparation of crystalline form A of the compound of formula 1 87.4 mg of the amorphous form of the compound of formula 1 was suspended in 200 μL of a 2:1 mixture of methanol / water at room temperature. A sticky substance formed but did not dissolve completely. After two hours of stirring, a very concentrated suspension was formed and 1 mL of the methanol / water mixture was added. After three days of stirring, the suspension was filtered using a centrifugal unit filter (PVDF, 0.22 μm, 5 min, 5000 rpm). The vial was rinsed with mother liquor. The recovered powder was designated sample 19 and was subjected to XRPD, which corresponded to crystalline form A (see FIG. 14).

[0342] Example 17: Preparation of crystalline form A of the compound of formula 1 72 mg of the amorphous form of the compound of formula 1 was suspended in 200 μL of 2-propanol / heptane 1:1 mixture at room temperature. A cloudy solution containing oil droplets was formed. After two hours of stirring, a very concentrated suspension was formed and 0.5 mL of 1-propanol / water mixture was added. A solution was obtained and further stirred at room temperature. After three days, no suspension was formed and the solution was further stirred at 5° C. After three days of stirring, a suspension was formed at 5° C. and filtration was performed using a centrifugal unit filter (PTFE, 0.22 μm, 5 min, 5000 rpm, 5° C.). The wet filter cake was designated sample 20 and was subjected to XRPD, which corresponded to crystalline form A (see Figures 7 and 14).

[0343] Example 18: Preparation of crystalline form A of the compound of formula 1 79 mg of the amorphous form of the compound of formula 1 was suspended in 200 μL of 1:1 1-propanol / water mixture at room temperature. A cloudy solution containing oil droplets was formed. After two hours of stirring, a very concentrated suspension was formed and 1 mL of 1-propanol / water mixture was added. After three days of stirring, the suspension was filtered using a centrifugal unit filter (PVDF, 0.22 μm, 5 min, 5000 rpm). The vial was rinsed with mother liquor. The recovered powder was designated sample 21 and was subjected to XRPD, which corresponded to crystalline form A (see FIG. 14).

[0344] Example 19: Preparation of crystalline form A of the compound of formula 1 41.8 mg of sample 18 and 31.6 mg of sample 19 (total 73.4 mg, crystalline form A) were suspended in 0.6 mL of heptane / acetone 9:1 mixture at room temperature. After stirring for 5 min, the suspension was seeded with sample 10 (crystalline form B). After stirring for 5 days at room temperature, the suspension was filtered using a centrifugal unit filter (PTFE, 0.22 μm, 5 min, 5000 rpm). The vial was rinsed with mother liquor. The recovered wet powder was designated sample 23 and was subjected to XRPD, which corresponded to crystalline form A (see FIG. 14).

[0345] Example 20: Preparation of Crystalline Form B of the Compound of Formula 1 97 mg of the amorphous form of the compound of formula 1 was dissolved in 500 μL of TBME at room temperature. The vial was opened and the solvent was evaporated. After 4 days, a dry residue was obtained and scraped off with a spatula. The resulting powder was designated sample 26 and was subjected to XRPD, which corresponds to crystalline form B (see FIG. 8).

[0346] Example 21: Preparation of crystalline form A of the compound of formula 1 500 μL of a 1:1 mixture of methanol / water was added to 101.2 mg of the amorphous form of the compound of formula 1. A sticky substance formed and the mixture was heated to 60° C. After stirring for 10 minutes, the sticky substance turned into a white solid and 200 μL of methanol was added. No change was observed. After vortexing, a suspension was obtained and further stirred at 60° C. After stirring for 4 days, a solution containing the substance on the glass side was obtained. The mixture was vortexed to obtain a suspension. After stirring for another 5 hours, the suspension was filtered using a centrifugal unit filter (PTFE, 0.22 μm, 5 min, 5000 rpm). The vial was rinsed with mother liquor. The recovered wet powder was designated sample 28 and was subjected to XRPD, which corresponded to crystalline form A (see FIG. 14).

[0347] Example 22: Preparation of crystalline form B of the compound of formula 1 500 μL of acetone / heptane 1:1 mixture was added to 99.4 mg of the amorphous form of the compound of formula 1 and the mixture was heated to 60° C. At 60° C., a solution was obtained. Then, heating was stopped and the temperature was allowed to cool to room temperature. At room temperature, a solution was still observed, so further stirring was performed at 5° C. After stirring for 4 days at 5° C., no precipitation was observed, so the vial was placed in a freezer (−26° C.) overnight. However, no precipitation occurred, so 0.5 mL of heptane was added to give a 1:3 ratio of acetone / heptane. No precipitation was observed, so further stirring was performed at 5° C. After stirring for 5 hours at 5° C., no change was observed. Therefore, the solution was seeded with sample 2 (crystal form A) and sample 10 (crystal form B). After stirring overnight at 5° C., a solution was still observed. 0.5 mL of heptane was slowly added at room temperature to give a 1:5 ratio of acetone / heptane. No precipitation was observed. The vial was opened and the solvent was evaporated with stirring. After 2 hours, only a small amount had evaporated, giving a suspension. It was filtered using a centrifugal unit filter (PTFE, 0.22 μm, 5 min, 5000 rpm). The vial was rinsed with mother liquor. The recovered wet powder was designated sample 30 and subjected to XRPD, which corresponds to crystalline form B. The remainder of sample 30 was dried at room temperature under reduced pressure (<5 mbar) for two days. The dried remainder was designated sample 30a. DSC analysis of sample 30a showed a melting peak at 131° C. with an onset of 124.8° C. and an enthalpy of 58.2 J / g (see FIG. 21).

[0348] Example 22: Preparation of crystalline form A of the compound of formula 1 1 mL of ethanol / water 2:1 mixture was added to 413.5 mg of the amorphous form of the compound of formula 1. After stirring for two minutes at room temperature, a solution containing a sticky material was observed. After 30 minutes of stirring, a very concentrated suspension was observed, so 2 mL of the solvent mixture was added. After stirring for three days at room temperature, the suspension was filtered using a centrifugal unit filter (PVDF, 0.22 μm, 5000 rpm, 5 min). The vial was rinsed with mother liquor. The recovered powder, designated sample 37, was placed in a vial and dried overnight at room temperature and 5 mbar vacuum, then subjected to XRPD, which corresponded to crystalline form A (see Figures 25-28).

[0349] Example 23a: Milling Experiments 75 mg of sample 37 was placed in a mortar and ground using a pestle. Three 1 minute grinding steps were performed, with the powder being centered and combined with a spatula between each grinding step. At the end of the experiment, the powder, designated sample 38, was scraped off with a spatula and subjected to XRPD (see Figures 25 and 26), which corresponded to crystalline form A but had broader and less intense reflections, suggesting loss of crystallinity. The elevated baseline suggests non-crystallization.

[0350] Example 23b: Ball Mill Experiments 75 mg of sample 37 was placed in a container with two 3 mm diameter grinding balls. Three 5 min grinding steps were performed, each at 30 / s. -1 This powder, designated sample 39, stuck to the edges of the container, was scraped off with a spatula, and subjected to XRPD, which corresponded to crystalline form A, although the peak intensities were slightly reduced (see Figures 25 and 27).

[0351] Example 23c: IR Press Experiments Approximately 100 mg of sample 37 was placed between two plungers (metal cylinders) in an IR press die set. The sample was compressed in the IR press for 5 minutes at 15 bar. The recovered powder, designated sample 40, was scraped off the cylinder with a spatula and subjected to XRPD (see Figures 25 and 38), which corresponded to crystalline form A, but with broader and less intense peaks, suggesting loss of crystallinity. The elevated baseline suggests non-crystallization.

[0352] Example 24a: Preparation of Crystalline Forms A and B of the Compound of Formula 1 1.1714 g of the amorphous form of the compound of formula 1 was placed in a 25-mL reaction vessel with a magnetic stir bar in an EasyMax 102 apparatus. To the powder, 15 mL of a 1:1 mixture of 2-propanol / water was added. A sticky substance formed at the bottom of the vial. A turbidity probe was placed in the reaction vessel. Stirring was started at 500 rpm, but the magnetic stir bar was blocked by the sticky substance. A spatula was used to "break" this blockage. After 2 minutes of stirring, a suspension formed. Heating was started to 60° C. at 1 K / min. At 60° C., a fine suspension was obtained. 2 mL of a 1:1 mixture of 2-propanol / water was added and the temperature was increased to 65° C. A solution was obtained at 65° C. and cooling was started to 5° C. at 0.2 K / h. After stirring overnight, the cooling rate was changed to 5 K / h. The resulting suspension was further stirred at 5° C. for 8 hours. Stirring was observed to stop as the magnetic stir bar was blocked by the thickened suspension. Filtration was performed on a fritted glass filter (porosity 4). The reaction vessel was rinsed with 3 mL of mother liquor. The cake was dried on the filter by applying vacuum for about 30 minutes. 1.4266 g of a white powder was recovered. Further drying was then performed at room temperature under reduced pressure (<5 mbar). 1.0196 g of powder was recovered after drying overnight. Yield: 87%

[0353] The XRPD pattern (see Figures 46, 47) corresponds to crystalline form A with a small amount of crystalline form B (seen at 19.2° and 21.5° 2θ). Small crystals were observed under an optical microscope. The shape could not be determined (see Figure 35). Crystalline forms A and B of Example 24a are referred to herein as Sample 43.

[0354] Example 24b: Preparation of crystalline form A of the compound of formula 1 1.1415 g of the amorphous form of the compound of formula 1 was placed in a 25-mL reaction vessel with a magnetic stir bar in an EasyMax 102 apparatus. To the powder, 18 mL of a 1:3 mixture of ethyl acetate / heptane was added. A sticky substance formed at the bottom of the vial. A turbidity probe was placed in the reaction vessel. Stirring was started at 500 rpm, but the magnetic stir bar was blocked by the sticky substance. A spatula was used to "break" this blockage. After 2 minutes of stirring, a suspension formed. Heating was started to 60° C. at 1 K / min. At 60° C., a suspension was obtained, so cooling was started to 5° C. at 0.2 K / h. After stirring overnight, the cooling rate was changed to 5 K / h. The resulting suspension was stirred for an additional 9 hours at 5° C. Cessation of stirring was observed as the magnetic stir bar was blocked by the thickened suspension. Filtration was performed on a fritted glass filter (porosity 4). The reaction vessel was rinsed with 3 mL of mother liquor. The cake was dried on the filter by applying vacuum for about 30 minutes. 694.2 mg of white powder was recovered. Further drying was then carried out at room temperature under reduced pressure (<5 mbar). After drying overnight, 692.1 mg of powder was recovered. Yield: 61%

[0355] The XRPD pattern corresponds to crystalline form A (see Figure 51). Small crystals (needle / columnar shaped) were observed under an optical microscope (see Figure 36). Crystalline form A of Example 24b is referred to herein as Sample 44.

[0356] Example 24c: Preparation of crystalline form A of the compound of formula 1 1.0314 g of the amorphous form of the compound of formula 1 was placed in a 25-mL reaction vessel with a magnetic stir bar in an EasyMax 102 apparatus. To the powder, 9 mL of 2-propanol was added. Stirring was started at 500 rpm and most of the material dissolved, but some sticky material formed. Heating was started at 1 K / min to 60° C. At 60° C., a clear solution was obtained and sticky material was no longer observed. 9 mL of water was added at 0.5 mL / min. After about 7 mL of water was added, localized precipitation was observed but did not persist. After the addition, the solution was observed at 60° C. Cooling was started to 5 K / h to 23° C. At about 43° C., a cloudy solution was observed and seeded with about 5 mg of sample 42. The seed did not dissolve. At 42° C., a thick suspension formed. After stirring overnight at 23° C., a thick suspension was obtained and stirring was difficult, so the stirring speed was increased to 1000 rpm. After stirring for 1 h, the suspension was filtered on a fritted glass (porosity 4). The reaction vessel was rinsed with 3 mL of mother liquor. The cake was dried on the filter by applying vacuum for about 30 min. 893.2 mg of a white powder was recovered. Further drying was then performed at room temperature under reduced pressure (<5 mbar). After drying overnight, 889.9 mg of powder was recovered. Yield: 86.3%.

[0357] The XRPD pattern corresponds to crystalline form A (see Figure 47). Small crystals (needle / columnar shaped) were observed under an optical microscope (see Figure 37). Crystalline form A of Example 24c is referred to herein as Sample 45.

[0358] Example 24d: Preparation of crystalline form A of the compound of formula 1 1.0063 g of the amorphous form of the compound of formula 1 was placed in a 25-mL reaction vessel with a magnetic stir bar in an EasyMax 102 apparatus. To the powder, 4 mL of ethyl acetate was added. Most of the material dissolved, but some sticky material formed. Stirring was started at 500 rpm and all the material dissolved. Heating was started at 1 K / min up to 60° C. At 60° C., a clear solution was obtained, so 16 mL of heptane was added at 0.5 mL / min. After the addition, a solution was observed at 60° C. Cooling was then started at 5 K / h to 23° C. At 47° C., the solution was seeded with about 5 mg of sample 42, forming a cloudy solution. After stirring overnight at 23° C., the suspension was filtered on a fritted glass (porosity 4). The reaction vessel was rinsed with 3 mL of mother liquor. The cake was dried on the filter by applying vacuum for about 30 minutes. 714.9 mg of white powder was recovered. Further drying was then carried out at room temperature under reduced pressure (<5 mbar). After drying overnight, 710 mg of powder was recovered. Yield: 70.6%

[0359] The XRPD pattern corresponds to crystalline form A (see Figure 47). Small crystals (needle / columnar shaped) were observed under an optical microscope (see Figure 38). Crystalline form A of Example 24d is referred to herein as Sample 46.

[0360] Example 24e: Preparation of crystalline form A of the compound of formula 1 994.9 mg of the amorphous form of the compound of formula 1 was placed in a 25-mL reaction vessel with a magnetic stir bar in an EasyMax 102 apparatus. To the powder, 6 mL of 2-propanol was added. Stirring was started at 500 rpm and most of the material dissolved, but some sticky material formed. The temperature was raised to 30° C., resulting in a cloudy solution. An additional 1 mL of 2-propanol was added, resulting in a clear solution (some particles did not dissolve). 8 mL of water was added at 0.5 mL / min, and localized precipitation was observed after each drop. Seeding with approximately 5 mg of sample 42 was performed after adding 1 mL of water. The seed did not dissolve. After the addition of water, the solution was observed at 30° C. Cooling was started to 25° C. at 5 K / h. After stirring at 25° C. for 1 h, the suspension was filtered on a fritted glass (porosity 4). The reaction vessel was rinsed with 3 mL of mother liquor. The cake was dried on the filter with vacuum applied for about 30 minutes. 1.0197 g of a white powder was recovered. Further drying was then carried out at room temperature under reduced pressure (<5 mbar).

[0361] 887.4 mg of powder was recovered after drying overnight. Yield: 89.2% The XRPD pattern corresponds to crystalline form A (see FIG. 47). Small crystals were observed under an optical microscope. The shape could not be determined (see FIG. 39). Crystalline form A of Example 24e is referred to herein as Sample 47.

[0362] Example 24f: Preparation of crystalline form A of the compound of formula 1 1.002 g of the amorphous form of the compound of formula 1 was placed in a 25-mL reaction vessel with a magnetic stir bar in an EasyMax 102 apparatus. To the powder, 2 mL of 2-propanol was added, forming a sticky material. Stirring was started at 500 rpm and heating was started to 60° C. at 1 K / min. A cloudy solution was observed at room temperature, and a suspension was obtained at about 38° C. A clear solution was observed at 60° C., and 3 mL of water was added at 0.1 mL / min. The stirring speed was increased to 700 rpm. After the addition of water, a fine suspension was obtained, so seeding was performed with about 5 mg of sample 42. Further stirring was continued for 30 min at 60° C., after which cooling was started to 22° C. at 2 K / h. The suspension was then filtered on a fritted glass (porosity 4). The reaction vessel was rinsed twice with 3 mL of mother liquor. The cake was dried on the filter by applying vacuum for about 30 min. 1.3642 g of white powder was recovered. Further drying was then carried out at room temperature under reduced pressure (<5 mbar). 912.5 mg of powder was recovered after drying overnight. Yield: 91%

[0363] The XRPD pattern corresponds to crystalline form A (see Figure 47). Small crystals were observed under an optical microscope. The shape could not be determined (see Figure 40). Crystalline form A of Example 24f is referred to herein as Sample 48. Figure 48 illustrates this example as follows: temperature (blue curve) and turbidity (green curve) as a function of time. The orange mark represents the seeding point.

[0364] Example 24g: Preparation of crystalline form A of the compound of formula 1 1.0147 g of the amorphous form of the compound of formula 1 was placed in a 25-mL reaction vessel with a magnetic stir bar in an EasyMax 102 apparatus. To the powder, 2 mL of 2-propanol was added, forming a sticky material. Stirring was started at 500 rpm and heating was started to 60° C. at 1 K / min. A clear solution was observed at 60° C., so 4 mL of water was added at 0.1 mL / min. The stirring speed was increased to 700 rpm. After the addition of water, a fine suspension was obtained, so seeding was performed with about 5 mg of sample 42. Further stirring was continued at 60° C. for 30 min, after which cooling was started to 22° C. at 2 K / h. After stirring overnight, the reaction vessel temperature was still at 60° C., and no cooling program was started. A suspension was already observed at 60° C. Cooling was started to 22° C. at 10 K / h, then the suspension was further stirred at 22° C. for 1 h 30 min. The suspension was filtered on a fritted glass filter (porosity 4). The reaction vessel was rinsed with 3 mL of mother liquor. The cake was dried on the filter by applying vacuum for about 1 h. 923.4 mg of a white powder was recovered. Further drying was then carried out at room temperature under reduced pressure (<5 mbar). 921.5 mg of powder was recovered after drying overnight. Yield: 91%

[0365] The XRPD pattern corresponds to crystalline form A (see Figure 47). Small crystals were observed under an optical microscope. The shape could not be determined (see Figure 41). Crystalline form A of Example 24g is referred to herein as Sample 49 (see Figure 41).

[0366] Example 24h: Preparation of crystalline form A of the compound of formula 1 1.0088 g of the amorphous form of the compound of formula 1 was placed in a 25-mL reaction vessel with a magnetic stir bar in an EasyMax 102 apparatus. 2 mL of 2-propanol was added to the powder, forming a sticky material. Stirring was started at 500 rpm and heating was started to 60° C. at 1 K / min. A clear solution was observed at 60° C. and 4 mL of water was added at 0.1 mL / min. The stirring speed was increased to 700 rpm. After the addition of water, a fine suspension was obtained and seeding was performed with sample 42 (approximately 5 mg). Stirring was continued for another 1 h 30 min at 60° C. and the stirring speed was changed to 700 rpm. Cooling was started to 20° C. at 2 K / h. The following temperature cycle was then programmed over the weekend: - Wait 1 hour at 20℃ - Heat to 40°C at 15K / h - Cool to 20°C at 5K / hour

[0367] These three steps were repeated four times. The suspension was then stirred at 1000 rpm at 20° C. for 1 day. Filtration was performed on a fritted glass filter (porosity 4). The reaction vessel was rinsed with 3 mL of mother liquor. The cake was dried on the filter by applying vacuum for about 30 min. 972.5 mg of a white powder was recovered. Further drying was then performed at room temperature under reduced pressure (<5 mbar).

[0368] After drying overnight, 927.8 mg of powder was recovered. Yield: 92%

[0369] Figure 49 illustrates this example: temperature (blue curve) and turbidity (green curve) as a function of time. Grey marks represent seeding points.

[0370] The XRPD pattern corresponds to crystalline form A (see FIG. 47). Small crystals were observed under an optical microscope. The shape could not be determined (see FIG. 42). Crystalline form A of Example 24h is referred to herein as Sample 50.

[0371] Example 24i: Preparation of crystalline form A of the compound of formula 1 1.0056 g of the amorphous form of the compound of formula 1 was placed in a 25-mL reaction vessel with a magnetic stir bar in an EasyMax 102 apparatus. To the powder, 2 mL of ethyl acetate was added, forming a sticky material. Stirring was started at 500 rpm and heating was started to 60° C. at 1 K / min. At 60° C., a clear solution was observed and 8 mL of heptane was added at 0.1 mL / min. The stirring speed was increased to 700 rpm. After heptane addition, a clear solution was observed and seeding was performed with sample 42 (approximately 5 mg). The seed did not dissolve, so cooling was started to 20° C. at 2 K / h. The following temperature cycle was then programmed to run over the weekend: - Wait 1 hour at 20℃ - Heat to 40°C at 15K / h - Cool to 20°C at 5K / hour

[0372] These three steps were repeated four times. The suspension was then stirred at 1000 rpm at 20° C. for 1 day. Filtration was performed on a fritted glass filter (porosity 4). The reaction vessel was rinsed with 3 mL of mother liquor. The cake was dried on the filter by applying vacuum for about 30 min. 902.7 mg of a white powder was recovered. Further drying was then performed at room temperature under reduced pressure (<5 mbar). 900.9 mg of powder was recovered after drying overnight. Yield: 90%

[0373] Figure 49 illustrates this example: temperature (blue curve) and turbidity (green curve) as a function of time. Grey marks represent seeding points.

[0374] The XRPD pattern corresponds to crystalline form A (see FIG. 47). Small crystals (needle / columnar shaped) were observed under an optical microscope (see FIG. 43). Crystalline form A of Example 24i is referred to herein as Sample 51.

[0375] Example 24j: Preparation of crystalline form A of the compound of formula 1 1.0120 g of the amorphous form of the compound of formula 1 was placed in a 25-mL reaction vessel with a magnetic stir bar in an EasyMax 102 apparatus. To the powder, 2 mL of 2-propanol was added, forming a sticky material. Stirring was started at 500 rpm and heating was started to 60 °C at 1 K / min. A clear solution was observed at 60 °C, so 4 mL of water was added at 1 mL / min. The stirring speed was increased to 700 rpm. After the addition of water, a suspension was obtained and seeding was performed with sample 42. The stirring speed was changed to 700 rpm and cooling was started to 20 °C at 10 K / h. After stirring at 20 °C for 2 days and 17 hours (65 hours in total), the suspension was filtered on a fritted glass filter (porosity 4). The reaction vessel was rinsed with 4 mL of mother liquor. The cake was dried on the filter by applying vacuum for about 1 hour. 956.3 mg of white powder was recovered. Further drying was then carried out at room temperature under reduced pressure (<5 mbar). 938.6 mg of powder was recovered after drying overnight. Yield: 93%

[0376] The XRPD pattern corresponds to crystalline form A (see FIG. 47). Small crystals were observed under an optical microscope. The shape could not be determined (see FIG. 44). Crystalline form A of Example 24j is referred to herein as Sample 52.

[0377] Example 24k: Preparation of crystalline form A of the compound of formula 1 40.0370 g of the amorphous form of the compound of formula 1 was placed in a 400-mL reaction vessel in an EasyMax 402 apparatus equipped with an anchor-type stirrer. To the slightly orange powder, 80 mL of 2-propanol was added. Stirring was set to 100 rpm and heating was started to 60° C. at 1 K / min. At 60° C., a clear orange solution was observed, so 160 mL of water was added at 1 mL / min. After the addition of about 90 mL of water, a cloudy solution was observed. A fine suspension was observed after the water addition. After further stirring at 60° C., a suspension was formed. Seeding was performed with sample 46 (about 40 mg). The suspension was further stirred at 60° C. for 30 min and the stirring speed was changed to 200 rpm. Cooling was then started to 20° C. at 2 K / h. The following temperature cycle was programmed over the weekend: - Wait 1 hour at 20℃ - Heat to 40°C at 15K / h - Cool to 20°C at 5K / hour

[0378] These three steps were repeated three times. The suspension was then stirred at 200 rpm at 20° C. for one day. Filtration was performed on a fritted glass filter (porosity 4). The reaction vessel was rinsed with 25 mL of mother liquor and the cake was washed with 30 mL of 2-propanol (2-prOH) / water 1:2 mixture. The cake was dried on the filter by applying vacuum for about 2 hours. 38.9163 g of white powder was recovered. Further drying was then performed at room temperature under reduced pressure (<5 mbar). 38.74 g of powder was recovered after drying overnight. Yield: 96.8%

[0379] The XRPD pattern corresponds to crystalline form A (see Figures 52 and 53). Small crystals were observed under an optical microscope. The shape could not be determined (see Figure 54). 1 H-NMR analysis shows that the NMR spectrum is consistent with the amorphous form of the compound of Formula 1, but contains little impurities (see Figures 56 and 57). A small amount of 2-propanol is seen. HPLC analysis shows a purity of 98 area % (see Figure 58). Thermogravimetric analysis (TG-FTIR) shows that a small amount of water was observed between 25 and 200°C (see Figure 55). Crystalline Form A of Example 24k is referred to herein as Sample 53. Figure 50 shows a graphical representation of this example, showing the temperature, amount of water, and particle number curves as a function of time. Figure 51 shows a graphical representation of this example, showing the mean square and particle number curves as a function of time.

[0380] Example 24l: Preparation of crystalline form A of the compound of formula 1 35.1697 g of the amorphous form of the compound of formula 1 was placed in a 400-mL reaction vessel in an EasyMax 402 apparatus equipped with an anchor-type stirrer. To the slightly orange powder, 70 mL of ethyl acetate was added. The stirring was set to 100 rpm and heating was started to 60° C. at 1 K / min. At 60° C., a clear orange solution was observed, so 280 mL of heptane was added at 2 mL / min. After the addition, a clear solution was obtained, so seeding was performed with sample 46 (about 40 mg). (Figure 60 shows the crystals immediately after seeding.) The seed crystals did not dissolve and a suspension was formed. The suspension was stirred for another 30 min at 60° C. and the stirring speed was changed to 200 rpm. Cooling was then started to 20° C. at 2 K / h. (Figure 61 shows the crystals after suspension formation when the cooling ramp was started.) The following temperature cycle was programmed over the weekend: - Wait 1 hour at 20℃ - Heat to 40°C at 15K / h - Cool to 20°C at 5K / hour

[0381] These three steps were repeated three times. (Figure 62 shows the suspension at the end of the process.) The suspension was then stirred at 200 rpm at 20°C for a day. Filtration was performed on a fritted glass filter (porosity 4). The reaction vessel was rinsed with 25 mL of mother liquor and the cake was washed with 30 mL of ethyl acetate / heptane 1:4 mixture. The cake was dried on the filter by applying vacuum for about 2 hours. 30.8252 g of white powder was recovered. Further drying was then performed at room temperature under reduced pressure (<5 mbar). 30.7783 g of powder was recovered after drying overnight. Yield: 87.5%

[0382] The XRPD pattern corresponds to crystalline form A (see Figures 63 and 64). Small crystals (needle / columnar shaped) were observed under an optical microscope (see Figure 65). 1H-NMR analysis shows that the NMR spectrum is consistent with the amorphous form of the compound of Formula 1, but contains little to no impurities (see Figure 67). HPLC analysis shows a purity of 98.7 area % (see Figure 68). Thermogravimetric analysis (TG-FTIR) shows that a small amount of water was observed between 25 and 200°C (see Figure 66). The crystalline form A of Example 24l is referred to herein as Sample 54. Figure 59 shows a graphical representation of this example with temperature, loading, turbidity, and particle number curves as a function of time.

[0383] Example 25a: Preparation of crystalline form B of the compound of formula 1 83.5 mg of the amorphous form of the compound of formula 1 was dissolved in 500 μL of methanol at room temperature. The vial was opened and the solvent was evaporated at room temperature. After three days, a glassy residue was obtained and further evaporated under a stream of nitrogen. After 5 hours, the glassy residue was collected with a spatula and subjected to XRPD analysis (see Figures 8, 9, 24, 46, 47, 53, and 64). Crystalline form B of Example 25a is referred to herein as Sample 10. 1 H-NMR analysis showed that the NMR spectrum of Sample 10 was consistent with that of the amorphous form of the compound of Formula 1, with residual 2-propanol (0.014 equiv.) and residual methanol (0.5 equiv.). DVS analysis showed a water uptake of 1.2% at 95% relative humidity at five hours (see Figures 22 and 23).

[0384] Example 25b: Preparation of crystalline form B of the compound of formula 1 The remainder of Sample 10 from Example 25a was dried overnight at room temperature at 5 mbar. Crystalline Form B from Example 3b is referred to herein as Sample 10a. The XRPD pattern of Sample 10a corresponded to that of Sample 10 (see Figures 19, 24, 30). Thermogravimetric analysis (TG-FTIR) showed a water weight loss of 0.80% from 25 to 250 °C (see Figure 11). DSC analysis showed a ΔC of 0.2 J / (g °C). p The step showed a glass transition at 59° C., a melting point of 132.5° C., an onset of 124° C., and a melting enthalpy of 45.7 J / g (see FIG. 20).

[0385] Example 26a: Preparation of crystalline form C of the compound of formula 1 One gram of amorphous compound of formula 1 was dissolved in ethyl acetate / n-heptane (16V, 1 / 3 v / v) at 60° C. and then cooled to 50° C. over 1 hour. After holding for 18 hours, a small amount was set aside, filtered, and submitted for XRPD analysis (see Figures 69, 70, 75, 76). After confirming that crystalline form C was obtained, the batch was concentrated to 1V at 45° C. and exchanged with heptane (5v×2) to a final volume of 5V, then filtered at 20-25° C. and dried in an oven at 45° C. for 18 hours. DSC analysis showed a melting peak at 142.8° C., an onset at 139.7° C., and the melting enthalpy was 58.3 J / g (see Figure 71).

[0386] Scanning electron microscopy (SEM) was performed on crystalline form C of compound of Formula 1. Six different magnifications were used: 100×, 250×, 500×, 1000×, 3000×, and 9000×. SEM images at 100× and 250× are shown in FIG. 72, SEM images at 500× and 1000× are shown in FIG. 73, and SEM images at 3000× and 9000× are shown in FIG. 74.

[0387] Crystalline Form C of Example 26a is referred to herein as Sample 55.

[0388] Example 26b: Preparation of crystalline form C of the compound of formula 1 One gram of amorphous compound of formula 1 was dissolved in 16 mL of ethyl acetate / heptane 1:3 (v / v) mixture at 60° C. A solution was obtained and the temperature was reduced to 50° C. in 1 hour. After stirring overnight (approximately 18 hours), a suspension was formed and 1.5 mL of the suspension was filtered and subjected to XRPD analysis. Crystalline form C was obtained.

[0389] The temperature was then reduced to 45° C. and the reaction vessel was opened to distill off the solvent. After stirring overnight, only 3 mL had distilled off, which was further distilled off with a stream of nitrogen. After 4 hours, the remaining solvent was about 5 volumes, and 10 mL of heptane was added slowly. The resulting suspension was stirred at 45° C. for 1 hour. Distillation was then started at 45° C. with a weak stream of nitrogen. After stirring overnight, about 8 volumes of suspension remained. The suspension was filtered on a fritted glass (porosity 4). The cake was dried on the filter by applying a vacuum. The powder was subjected to XRPD analysis, giving crystalline form C.

[0390] Crystalline form C of Example 26b is referred to herein as Sample 60.

[0391] Example 27a: Competitive Slurry Equilibrium Experiments 53 mg of sample 42 (form A) and 47 mg of sample 42 (form C) were suspended in 1 mL of ethyl acetate / heptane (1:3) mixture at room temperature. After stirring for two hours at room temperature, an additional 1 mL of the solvent mixture was added to the suspension. After stirring for an additional hour, the suspension was seeded with sample 42 and sample 55 (approximately 10-20 mg). Stirring was continued at room temperature for an additional week. The suspension was then filtered using a centrifugal unit filter (PTFE, 0.2 μm, 5000 rpm, room temperature). The recovered filter cake was subjected to XRPD analysis, which showed a pattern corresponding to a mixture of forms A and C. This resulting mixture of forms A and C is referred to herein as sample 56.

[0392] The remaining material from Sample 56 (approximately 42 mg) was further equilibrated in 0.5 mL of ethyl acetate / heptane (1:3) mixture at room temperature. After stirring for one month, the suspension was filtered using a centrifugal unit filter (PTFE, 0.2 μm, 5000 rpm, room temperature). The recovered filter cake was subjected to XRPD analysis, which showed a pattern corresponding to crystalline form C. The resulting crystalline form C of this Example 27a is referred to herein as Sample 56A.

[0393] Example 27b: Competitive Slurry Equilibrium Experiments 71 mg of sample 42 (form A) and 73 mg of sample 55 (form C) were suspended in 1 mL of ethyl acetate / heptane (1:3) mixture at 60°C. After stirring for two hours at 60°C, an additional 1 mL of the solvent mixture was added to the suspension. After stirring for an additional hour, the suspension was seeded with sample 42 and sample 55 (approximately 10-20 mg). Further stirring was carried out at 60°C. After stirring for four days, a solution was obtained containing material on the glass side. Approximately 25 mg of sample 42 and 25 mg of sample 55 were added to obtain a suspension. After stirring for three more days at 60°C, the suspension was filtered using a centrifugal unit filter (PTFE, 0.2 μm, 5000 rpm, 40°C). The recovered filter cake was subjected to XRPD analysis, which showed a pattern corresponding to crystalline form C.

[0394] Crystalline form C of Example 27b is referred to herein as Sample 57.

[0395] Example 27c: Competitive Slurry Equilibrium Experiments 111 mg of sample 42 (crystal form A) and 121 mg of sample 55 (crystal form C) were suspended in 2 mL of ethyl acetate / heptane 1:3 mixture at 30° C. After stirring for 30 min, an additional 2 mL of the solvent mixture was added. After stirring for 1 h at 30° C., the suspension was seeded with sample 42 and sample 55 (approximately 10 mg of each sample). Further stirring was carried out at 30° C. for two weeks. Half of the suspension was then filtered using a centrifugal unit filter (PTFE, 0.2 μm, 5000 rpm, 30° C.). The recovered filter cake was designated as sample 63 and was subjected to XRPD analysis. The XRPD pattern corresponded to a mixture of crystal forms A and C (see FIG. 75).

[0396] The remaining half of the suspension was stirred for an additional four weeks (total stirring time six weeks). During equilibration, some material was again observed on the walls of the vial (just above the suspension), so the mixture was vortexed twice a day to bring all the material back into suspension. The suspension was then filtered using a centrifugal unit filter (PTFE, 0.2 μm, 5000 rpm, 30° C.). The recovered filter cake was designated as Sample 63A and was subjected to XRPD analysis. The XRPD pattern corresponded to Form C with a small amount of Form A (see FIG. 75).

[0397] Example 27d: Competitive Slurry Equilibrium Experiments 104 mg of sample 42 (form A) and 105 mg of sample 55 (form C) were suspended in 2 mL of ethyl acetate / heptane 1:3 mixture at 35° C. After stirring for 30 minutes, an additional 2 mL of the solvent mixture was added. After stirring for 1 hour at 35° C., the suspension was seeded with sample 42 and sample 55 (approximately 10 mg of each sample). Further stirring was continued at 35° C. for two weeks. Half of the suspension was then filtered using a centrifugal unit filter (PTFE, 0.2 μm, 5000 rpm, 35° C.). The recovered filter cake was designated as sample 64 and subjected to XRPD analysis. The XRPD pattern corresponded to form C with a small amount of form A (see FIG. 76).

[0398] The remaining suspension was stirred for an additional two weeks (total stirring time 1 month). The suspension was filtered using a centrifugal unit filter (PTFE, 0.2 μm, 5000 rpm, 35° C.). The collected filter cake was designated Sample 64A and subjected to XRPD analysis. The XRPD pattern corresponded to a mixture of Forms A and C, with an increased amount of Form A compared to Sample 64 (see FIG. 76).

[0399] The recovered filter cake from Sample 64A was further slurried in the recovered mother liquor at 35° C. Agitation continued for another two weeks (total agitation time was six weeks). During equilibration, some material was again observed on the walls of the vial (just above the suspension), so the mixture was vortexed twice a day to bring all the material back into suspension. The suspension was filtered using a centrifugal unit filter (PTFE, 0.2 μm, 5000 rpm, 35° C.). The recovered filter cake was designated Sample 64B and was submitted for XRPD analysis (see FIG. 76).

[0400] Example 27e: Competitive Slurry Equilibrium Experiments - Form A and Form B Competitive slurry equilibrium experiments were carried out on crystalline forms A and B of the compound of formula 1. Considering the high solubility of the amorphous starting material in common organic solvents, the competitive slurry experiments started with a suspension of crystalline form A, which was then seeded with crystalline form B or with a mixture of crystalline forms A and B. Thus, a mixture of water, heptane, and cyclohexane was chosen to reduce the solubility of the amorphous compound of formula 1 in pure organic solvents and obtain a suspension of crystalline form A.

[0401] In all experiments carried out, crystalline form A was obtained at the end of the equilibration time, and crystalline form B was no longer observed in the XRPD patterns. Thus, crystalline form A is the more stable form of crystalline forms A and B. [Table 4]

[0402] Example 27f: Competitive Slurry Equilibrium Experiments - Form A and Form C Competitive slurry equilibrium experiments were carried out on crystalline forms A and C of the compound of formula 1. [Table 5]

[0403] Those skilled in the art will recognize that the present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not limiting. The scope of the invention is therefore indicated by the appended claims rather than the foregoing description. All changes that come within the meaning and range of equivalency of the claims are to be embraced within the scope of the invention.

Claims

1. A crystalline form of the compound of formula 1, 【Chemical 1】 having peaks at 2θ values of ±0.2° of 18.1°, 19.5°, and 22.3°, and further optionally having peaks at 2θ values of ±0.2° selected from the group consisting of 3.5°, 7.1°, 8.9°, 9.1°, 9.6°, 10.7°, 12.6°, 14.0°, 16.9°, 18.4°, 18.9°, 20.1°, 21.0°, 22.0°, and 22.7°, characterized by a powder X-ray diffraction (XRPD) pattern.

2. The crystalline form according to claim 1, wherein the crystalline form is substantially pure.

3. A pharmaceutical composition comprising the crystalline form according to claim 1 or 2 as an active ingredient and at least one pharmaceutically acceptable carrier or diluent.

4. A method for preparing the crystalline form according to claim 1, the method comprising: dissolving the compound of formula 1 in one or more components A, optionally with stirring and / or heating, wherein the compound of formula 1 dissolved in the dissolving step is amorphous, one or more crystalline forms, or a combination thereof, and component A is an organic solvent suitable for dissolving the compound of formula 1, preferably C １ - C ４ alcohol, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, n - heptane, isobutyl acetate, MEK, methanol, medium-chain triglycerides, NMP, 1 - octanol, 1 - propanol, 2 - propanol, TBME, THF, toluene, and triethylamine, more preferably C １ - C ４A step of dissolving in one or more of alcohol, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium-chain triglyceride, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine, Optionally, a step of adding one or more component Bs, wherein component B is a poor solvent that reduces the solubility of the mixture, and component B is water and C ５ to C １２ One or more of the cyclic or acyclic hydrocarbon alkanes of (e.g., cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably including one or more of water and heptane, the step of adding.

5. A method for preparing the crystalline form according to claim 1, the method comprising: A step of dissolving the compound of formula 1 in one or more component As, which is optionally dissolved with stirring and / or heating, and the compound of formula 1 dissolved in the step of dissolving is amorphous, one or more crystalline forms, or a combination thereof, and component A is an organic solvent suitable for dissolving the compound of formula 1, preferably C １ to C ４ One or more of alcohol, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, n-heptane, isobutyl acetate, MEK, methanol, medium-chain triglyceride, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine, more preferably C １ to C ４A step of dissolving, which is one or more of alcohol, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium-chain triglyceride, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine; A step of adding one or more components B, wherein component B is a poor solvent that reduces the solubility of the mixture, and component B is water and C ５ ~C １２ A step of adding, which includes one or more of cyclic or acyclic hydrocarbon alkanes of C (for example, cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably including one or more of water and heptane; A method comprising the steps of filtering, washing, and drying the obtained solid.

6. A crystalline form of the compound of formula 1 prepared by the method according to claim 4.

7. A crystalline form of the compound of formula 1, wherein 【Chemical Formula 2】 It includes peaks at 2θ with values of ±0.2° of 4.6°, 20.5°, and 21.7°, and further may include peaks at 2θ with values of ±0.2° of one or more selected from the group consisting of 7.6°, 12.4°, 13.8°, 18.0°, 18.4°, and 20.0°, characterized by a powder X-ray diffraction (XRPD) pattern.

8. The crystalline form according to claim 7, wherein the crystalline form is substantially pure.

9. A pharmaceutical composition comprising the crystalline form according to claim 7 or 8 as an active ingredient and at least one pharmaceutically acceptable carrier or diluent.

10. The pharmaceutical composition according to claim 3, wherein the crystalline form constitutes 80% or more of the total amount of the compound of formula 1 in the pharmaceutical composition.

11. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is for treating pests in animals, optionally cats and / or dogs.

12. The pharmaceutical composition according to claim 3, wherein the pests include ticks and / or fleas.

13. A method for preparing the crystalline form according to claim 7 or 8, the method comprising: dissolving the compound of formula 1 in one or more component A, optionally with stirring and / or heating, wherein the compound of formula 1 dissolved in the dissolving step is amorphous, one or more crystalline forms, or a combination thereof, and component A is an organic solvent suitable for dissolving the compound of formula 1, preferably C １ ~C ４ alcohol, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, n-heptane, isobutyl acetate, MEK, methanol, medium-chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and one or more of triethylamine, more preferably C １ ~C ４ alcohol, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium-chain triglycerides, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and one or more of triethylamine, including the dissolving step, adding one or more component B, wherein component B is a poor solvent that reduces the solubility of the mixture, and component B is water and C ５~C １２ including one or more of cyclic or acyclic hydrocarbon alkanes (e.g., cyclohexane, hexane, heptane, n - heptane, octane, nonane, and decane), preferably including one or more of water and heptane, and may include a step of adding, including a step of distilling off the one or more component A and the one or more component B, A method including a step of filtering the obtained solid.

14. A method for preparing the crystalline form according to claim 7 or 8, the method comprising: a step of dissolving the compound of formula 1 in one or more component A, wherein the compound of formula 1 dissolved in the dissolving step is amorphous, one or more crystalline forms, or a combination thereof, and component A is an organic solvent suitable for dissolving the compound of formula 1, preferably C １ ~C ４ alcohol, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, n - heptane, isobutyl acetate, MEK, methanol, medium - chain triglyceride, NMP, 1 - octanol, 1 - propanol, 2 - propanol, TBME, THF, toluene, and triethylamine, more preferably C １ ~C ４ alcohol, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium - chain triglyceride, NMP, 1 - octanol, 1 - propanol, 2 - propanol, TBME, THF, toluene, and triethylamine, and a step of dissolving which is one or more of them, a step of adding one or more component B, wherein component B is water and C ５ ~C １２including one or more of cyclic or acyclic hydrocarbon alkanes (e.g., cyclohexane, hexane, heptane, n - heptane, octane, nonane, and decane), preferably including one or more of water and heptane, the step of adding; the step of stirring the solution formed from the step of dissolving; the step of distilling off the one or more component A and the one or more component B from the solution; the step of adding one or more additional component B; a method comprising the step of distilling off the one or more component A and the one or more component B from the solution containing the one or more additional component B.

15. A crystalline form of the compound of formula 1 prepared by the method according to claim 13.

16. A crystalline form of the compound of formula 1, 【Chemical Formula 3】 including peaks at 2θ values of ±0.2° of 3.5°, 19.2° and 22.3°, and further including peaks at 2θ values of ±0.2° selected from the group consisting of 7.1°, 9.1°, 9.4°, 9.8°, 10.6°, 11.1°, 13.5°, 17.7°, 18.0°, 18.6°, 18.9°, 19.5°, 19.8°, 20.3°, 21.0°, 21.5° and 22.7°, a crystalline form characterized by a powder X - ray diffraction (XRPD) pattern.

17. The crystalline form according to claim 16, wherein the crystalline form is substantially pure.

18. A pharmaceutical composition comprising the crystalline form according to claim 16 or 17 as an active ingredient and at least one pharmaceutically acceptable carrier or diluent.

19. The pharmaceutical composition according to claim 18, wherein the crystalline form constitutes 80% or more of the total amount of the compound of formula 1 in the pharmaceutical composition.

20. The pharmaceutical composition according to claim 18, wherein the pharmaceutical composition is for treating pests in animals, optionally cats and / or dogs.

21. The pharmaceutical composition according to claim 20, wherein the pest comprises fleas and / or ticks.

22. A method for preparing the crystalline form according to claim 16 or 17, the method comprising: dissolving the compound of formula 1 in one or more component A, optionally with stirring and / or heating, wherein the compound of formula 1 dissolved in the dissolving step is in amorphous form, one or more crystalline forms, or a combination thereof, and component A is an organic solvent suitable for dissolving the compound of formula 1, preferably C １ -C ４ alcohol, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, n-heptane, isobutyl acetate, MEK, methanol, medium-chain triglyceride, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine, more preferably C １ -C ４ alcohol, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium-chain triglyceride, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine, and comprising the dissolving step, adding one or more component B, wherein component B is a poor solvent that reduces the solubility of the mixture, and component B is water and C ５ -C １２It may include a step of adding, which includes one or more of cyclic or acyclic hydrocarbon alkanes (e.g., cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably including one or more of water and heptane. It includes a step of distilling off one or more component A and, when present, one or more component B. A method that includes a step of filtering the obtained solid.

23. The compound of formula 1 dissolved in the dissolving step is amorphous, one or more crystalline forms, or a combination thereof. Component A is an organic solvent suitable for dissolving the compound of formula 1, preferably C １ ~C ４ One or more of alcohol, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, cyclohexane, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, heptane, n-heptane, isobutyl acetate, MEK, methanol, medium-chain triglyceride, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine, more preferably C １ ~C ４ One or more of alcohol, acetone, acetonitrile, aniline, anisole, benzyl alcohol, butyronitrile, chloroform, DMSO, ethanol, ethyl acetate, isopropyl acetate, ethyl lactate, isobutyl acetate, MEK, methanol, medium-chain triglyceride, NMP, 1-octanol, 1-propanol, 2-propanol, TBME, THF, toluene, and triethylamine. The method includes a step of adding one or more component B, where component B is a poor solvent that reduces the solubility of the mixture, and component B is water and C ５ ~C １２The method according to claim 22, comprising one or more of cyclic or acyclic hydrocarbon alkanes (e.g., cyclohexane, hexane, heptane, n-heptane, octane, nonane, and decane), preferably comprising one or more of water and heptane.

24. A crystalline form of the compound of formula 1 prepared by the method according to claim 22.

25. The crystalline form according to claim 1 or 2, having an exothermic peak with a starting point at about 132 °C and a maximum point at about 136 °C in differential scanning calorimetry.

26. The method according to claim 5, wherein the volume ratio (v / v) of component A to component B is in the range of about 20:1 to about 1:20, optionally about 10:1 to about 1:10, optionally about 8:1 to about 1:8, optionally about 5:1 to about 1:5, optionally about 3:1 to about 1:3, optionally about 2:1 to about 1:

2.

27. The method according to claim 26, wherein the volume ratio (v / v) of component A to component B is about 3:1, about 2:1, about 1:1, about 4:5, about 1:3, or about 1:

10.

28. The method according to claim 13, wherein the volume ratio (v / v) of component A to component B is in the range of about 20:1 to about 1:20, optionally about 10:1 to about 1:10, optionally about 8:1 to about 1:8, optionally about 5:1 to about 1:5, optionally about 3:1 to about 1:3, optionally about 2:1 to about 1:

2.

29. The method according to claim 28, wherein the volume ratio (v / v) of component A to component B is about 3:1, about 2:1, about 1:1, about 4:5, about 1:3, or about 1:

10.

30. The method according to claim 23, wherein the volume ratio (v / v) of component A to component B is in the range of about 20:1 to about 1:20, optionally about 10:1 to about 1:10, optionally about 8:1 to about 1:8, optionally about 5:1 to about 1:5, optionally about 3:1 to about 1:3, optionally about 2:1 to about 1:

2.

31. The method according to claim 30, wherein the volume ratio (v / v) of component A to component B is about 3:1, about 2:1, about 1:1, about 4:5, about 1:3, or about 1:

10.

32. Use of the crystalline form according to any one of claims 1, 2, 6, 7, 8, 15, 16, 17, 24 and 25 in the manufacture of a medicament for the treatment and / or control of pests.

33. The use according to claim 32, wherein the pest is a flea, tick, mite, fly, worm, louse or a combination thereof.

34. A unit dosage form comprising the crystalline form according to any one of claims 1, 2, 6, 7, 8, 15, 16, 17, 24 and 25, wherein the amount of the crystalline form is about 1% to about 50%, optionally about 10% to about 35%, or optionally about 15% to about 25% of the weight of the unit dosage form.

35. The unit dosage form according to claim 34, comprising the crystalline form according to any one of claims 1, 2, 6, 7, 8, 15, 16, 17, 24 and 25 in an amount from 0.5 mg to about 100 mg.

36. A method for treating and / or controlling pests, comprising administering to a subject in need thereof an effective amount of the crystalline form according to any one of claims 1, 2, 6, 7, 8, 15, 16, 17, 24 and 25.

37. The method according to claim 36, further comprising administering an effective amount of at least one additional active compound or co-crystal.

38. The method according to claim 36 or 37, wherein the administration is oral or parenteral.

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